Compounds targeting proteins, compositions, methods, and uses thereof

ABSTRACT

The present invention provides compounds that modulate protein function, to restore protein homeostasis, including cytokine, CK1α, GSPT1, aiolos, and/or ikaros activity, and cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of diseases, disorders, or conditions associated with a protein, such as diseases, disorders, and conditions associated with cytokines, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn&#39;s disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer&#39;s disease, and cancer, are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/011,090, filed Jun. 18, 2018 and to be issued as U.S. Pat. No.10,336,771, which is a continuation of U.S. patent application Ser. No.15/847,628, filed Dec. 19, 2017, now U.S. Pat. No. 10,040,804, whichclaims the benefit of priority to U.S. Provisional Patent ApplicationNos. 62/437,400 filed Dec. 21, 2016, 62/485,563 filed Apr. 14, 2017, and62/538,203 filed Jul. 28, 2017, all of which are incorporated byreference herein in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

Compounds, methods of making such compounds, pharmaceutical compositionsand medicaments comprising such compounds, and methods of using suchcompounds to treat, prevent or diagnose diseases, disorders, orconditions associated with protein malfunction are provided.

Description of the Related Technology

Aberrant protein function, and/or protein imbalance is a hallmark ofmany disease states. For example, the functioning of the immune systemis finely balanced by the activities of pro-inflammatory andanti-inflammatory mediators or cytokines. Some cytokines promoteinflammation (pro-inflammatory cytokines), whereas other cytokinessuppress the activity of the pro-inflammatory cytokines(anti-inflammatory cytokines). For example, IL-4, IL-10, and IL-13 arepotent activators of B lymphocytes, and also act as anti-inflammatoryagents. They are anti-inflammatory cytokines by virtue of their abilityto suppress genes for pro-inflammatory cytokines such as IL-1, TNF, andchemokines.

Unregulated activities of these mediators can lead to the development ofserious inflammatory conditions. For example, autoimmune diseases arisewhen immune system cells (lymphocytes, macrophages) become sensitizedagainst the “self.” Lymphocytes, as well as macrophages, are usuallyunder control in this system. However, a misdirection of the systemtoward the body's own tissues may happen in response to stillunexplained triggers. One hypothesis is that lymphocytes recognize anantigen which mimics the “self” and a cascade of activation of differentcomponents of the immune system takes place, ultimately leading totissue destruction. Genetic predisposition has also been postulated tobe responsible for autoimmune disorders.

Tumor necrosis factor-alpha (TNF-alpha, or TNF-α) and interleukin-1(IL-1) are pro-inflammatory cytokines that mediate inflammatoryresponses associated with infectious agents and other cellular stresses.Overproduction of these cytokines is believed to underlie theprogression of many inflammatory diseases including rheumatoid arthritis(RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis,endotoxin shock, osteoporosis, Alzheimer's disease, congestive heartfailure, and psoriasis among others.

Recent data from clinical trials support the use of protein antagonistsof cytokines, for example soluble TNF-α receptor fusion protein(etanercept) or the monoclonal TNF-α antibody (infliximab), for thetreatment of rheumatoid arthritis, Crohn's disease, juvenile chronicarthritis and psoriatic arthritis. Thus, the reduction ofpro-inflammatory cytokines such as TNF-α and interleukin-1 (IL-I) hasbecome an accepted therapeutic approach for potential drug interventionin these conditions.

Moreover, IL-2 is now FDA approved for the treatment of renal cancer andmelanoma patients, with durable, complete remissions achieved with IL-2up to 148 months. However, the short half-life of IL-2 in serum requiresthat large amounts of IL-2 be injected to achieve therapeutic levels.Many attempts have been made to minimize side effects of systemic IL-2treatment, for example, introducing IL-2 directly into the tumor, thoughthis complicates treatment, and has largely been unsuccessful.

Local delivery of cytokines is appealing compared to systemic deliveryfor a variety of reasons. It takes advantage of the natural biology ofcytokines that have evolved to act locally in a paracrine or autocrinefashion. Local expression also dramatically minimizes many of the sideeffects of systemic delivery of cytokines. Thus, compounds and methodsto increase local expression of IL-2 would be better tolerated than highdose IL-2 treatment, which would expand therapeutic utility ofstrategies that increase IL-2.

Additional targets include several candidate genes involved in apoptosisand cell survival, including the translation termination factor GSPT1(eRF3a), casein kinase 1α (CK1α), and the zinc-finger transcriptionfactors aiolos, helios, and ikaros. Aiolos, helios, and ikaros aretranscription factors whose expression is restricted to lymphoidlineages. For example, aiolos binds to the Bcl-2 promoter, and alsointeracts with the Bcl-2 and Bcl-XL proteins to promote cell survival.Upregulation of aiolos expression, for example, can reduce apoptosis ofHIV-1 infected cells.

Likewise, expression of aiolos in lung and breast cancers predictssignificantly reduced patient survival. Aiolos decreases expression of alarge set of adhesion-related genes, disrupting cell-cell andcell-matrix interactions, facilitating metastasis. Aiolos may alsofunction as an epigenetic driver of lymphocyte mimicry in certainmetastatic epithelial cancers. Similarly, aberrant ikaros and heliosexpression may promote Bcl-XL expression, driving the development ofhematopoetic malignancies. Thus, down-regulation of aiolos, ikaros,and/or helios may reduce or eliminate metastasis.

GSPT1 mediates stop codon recognition and facilitates release of anascent peptide from the ribosome and is also involved in several othercritical cellular processes, such as cell cycle regulation, cytoskeletonorganization and apoptosis. Accordingly, decreased levels of GSPT1 mayimpair control of cell proliferation and facilitate cell migration andscar formation. Indeed, GSPT1 has been implicated as an oncogenic driverof several different cancer types, including breast cancer,hepatocellular carcinoma, gastric cancer, and prostate cancer. See,e.g., Brito, et al., Carcinogenesis, Vol. 26, No. 12, pp. 2046-49(2005); Brito, et al., Canc. Geneti. Cytogen., Vol. 195, pp. 132-42(2009); Tavassoli, et al., Med. Oncol., Vol. 29, pp. 1581-85 (2011);Wright and Lange, Rev. Urol., Vol. 9, No. 4, pp. 207-213 (2007);Hoshino, et al., Apoptosis, Vol. 17, pp. 1287-99 (2012); Liu, et. al.,PLOS One, Vol. 9, No. 1, e86371 (2014); and Jean-Jean, et al., Mol.Cell. Bio., Vol. 27, No. 16, pp. 5619-29 (2007). GSPT1 also contributesto glial scar formation and astrogliosis after a central nervous system(CNS) injury. See, e.g., Ishii et al., J. Biol. Chem., Vol. 292, No. 4,pp. 1240-50 (2017).

Casein kinase 1α (CK1α) is a component of the β-catenin-degradationcomplex and a critical regulator of the Wnt signaling pathway, and itsablation induces both Wnt and p53 activation. Schittek and Sinnberg,Mol. Cancer. 2014, 13, 231; Cheong and Virshup, J. Biochem. Cell Biol.2011, 43, 465-469; Elyada et al., Nature 2011, 470, 409-413. CK1αphosphorylates β-catenin, which is subsequently further phosphorylatedby GSK-3β. This destabilizes β-catenin and marks the protein forubiquitination and proteasomal degradation. Thus, CK1α functions as amolecular switch for the Wnt pathway. Amit et al., Genes Dev. 2002, 16,1066-1076. CK1α is critical for embryogenesis and plays an importantrole in tissue development and response to DNA damage, at least partlycoordinated with p53. Elyada et al., Nature 2011, 470, 409-413;Schneider et al., Cancer Cell 2014, 26, 509-520. Levine and Oren, Nat.Rev. Cancer 2009, 9, 749-758.

Indeed, CK1α also phosphorylates p53, which inhibits binding to MDM2 (ap53 inhibitor) and stabilizes p53's binding interactions with thetranscriptional machinery. Huart, et al., J. Biol. Chem. 2009, 284,32384-32394. Thus, inhibiting CK1α activity increases cellular levels ofp53. This is of particular importance for skin cancer, which has killedmore people since 1980 than all other types of cancer combined. Stern,Arch Dermatol. 2010, 146, 279-282.

In the skin, p53 also acts as a central player against UV damage via thep53/POMC/α-MSH/MC1R/MITF skin tanning pathway and through the DNArepair/cell cycle arrest/apoptotic pathway. Cui et al., Cell 2007, 128,853-864; Ogmundsdottir and Steingrimsson, Pigment. Cell Melanoma Res.2014, 27, 154-155. UV radiation can injure the skin both by indirectcellular damage via the generation of reactive oxygen species and bydirect damage to the structure of DNA. This damage may cause a sunburnreaction and ultimately the development of skin cancers. Keratinocytesin the epidermis are sensitive to UV radiation and are the majorresponders in the skin. Upon exposure to UV radiation, keratinocytesproduce various paracrine factors (for example, α-melanocyte stimulatinghormone (α-MSH), adrenocorticosteroid hormone (ACTH), endothelin-1(Edn1) and Kit) that activate adjacent melanocytes to increase melaninsynthesis. Natarajan et al., Nat. Chem. Biol. 2014, 10, 542-551; Kondo,J. Invest. Dermatol. Symp. Proc. 1999, 4, 177-183; Costin and Hearing,FASEB J. 2007, 21, 976-994; Costin and Hearing, FASEB J. 2007, 21,976-994; Cui et al., Cell 2007, 128, 853-864; Nasti and Timares,Photochem. Photobiol. 2015, 91, 188-200; Slominski et al., Physiol. Rev.2004, 84, 1155-1228; Murase et al., J. Biol. Chem. 2009, 284, 4343-4353;Hyter et al., Pigment. Cell Melanoma Res. 2013, 26, 247-258; D'Orazio etal., Nature 2006, 443, 340-344. In particular, p53 promotes UV-inducedskin pigmentation by stimulating the transcription of a melanogeniccytokine, POMC (pro-opiomelanocortin), in keratinocytes.

Skin hyperpigmentation, resulting from the increased synthesis ofmelanin in melanocytes followed by the distribution of melanin toneighboring keratinocytes, is one of the biological responses toexposure to UV radiation. Melanin acts as a natural sunscreen thatdirectly protects against UV and visible light radiation frompenetrating to deep skin layers, where proliferating cells reside, aswell as acting as a potent antioxidant and free-radical scavenger.Kadekaro et al., Pigment Cell Res. 2003, 16, 434-447. Individuals withdarker skin generally have a reduced incidence of UV-induced skincancers, whereas individuals with lighter skin are more prone toUV-induced damage and tumor formation and have weak tanning responses.Brenner and Hearing, Photochem. Photobiol. 2008, 84, 539-549.

Melanocytes produce two distinct types of melanin pigments: black-browneumelanin that is prevalent in individuals with black and/or brown hair,and yellow-reddish pheomelanin that is primarily produced in individualswith red hair and freckles. Costin and Hearing, FASEB J. 2007, 21,976-994; Slominski et al., Physiol. Rev. 2004, 84, 1155-1228; Prota,Pigment. Cell Res. 1992, Suppl. 2, 25-31. Pheomelanin is also producedin the skin of individuals that don't have red hair and freckles. Thodyet al., J. Invest. Dermatol. 1991, 97, 340-344. The beneficial effectsof melanin are mainly due to the presence of eumelanin that absorbs mostof the UV and scavenges the UV-generated free radicals, whereaspheomelanin is known to be carcinogenic. Brenner and Hearing, Photochem.Photobiol. 2008, 84, 539-549; Mitra et al., Nature 2012, 491, 449-453.

Therefore, there is a need for an effective method to increase thebeneficial level of eumelanin selectively to prevent UV-induced DNAdamage and skin cancers. Expression levels of proteins transcriptionallyupregulated by p53 are demonstrably higher in pigmented skin areasrelative to sun-protected controls.

One mechanism to disrupt protein drivers of disease is to decrease thecellular concentration of these proteins. For example, proteolyticdegradation of cellular proteins is essential to normal cell function.Hijacking this process, by targeting specific disease-related proteins,presents a novel mechanism for the treatment of disease. Theirreversible nature of proteolysis makes it well-suited to serve as aregulatory switch for controlling unidirectional processes. For example,increasing p53 levels by targeting CK1α for degradation may improve thepigmentation response to UV exposure, decreasing the risk of skincancer.

Ubiquitin-mediated proteolysis begins with ligation of one or moreubiquitin molecules to a particular protein substrate. Ubiquitinationoccurs through the activity of ubiquitin-activating enzymes (E1),ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3),acting sequentially to attach ubiquitin to lysine residues of substrateproteins. The E3 ligases confer specificity to ubiquitination reactionsby binding directly to particular substrates.

SUMMARY OF THE INVENTION

The compounds disclosed in the present application have been discoveredto exert surprising and unexpected biological effects. Some embodimentsprovide protein-targeting compounds (“targeting groups”). Someembodiments provide chimeric compounds comprising a targeting group, alinker group, and an E1-binding group. Some embodiments provide chimericcompounds comprising a targeting group, a linker group, and anE2-binding group. Some embodiments provide chimeric compounds comprisinga targeting group, a linker group, and an E3-binding group. Someembodiments provide chimeric compounds comprising a targeting group, alinker group, and a combination of one or more E1-, E2-, or E−3-bindinggroups.

Some embodiments provide compounds of Formula (II):

or pharmaceutically acceptable salts or solvates thereof.

In some embodiments, Q₁, Q₂, and Q₃ are each independently CR₁, CR₂, or—S—. In some embodiments, at least one of Q₁, Q₂, and Q₃ is CR₁ or CR₂.In some embodiments, each of Q₁, Q₂, and Q₃ cannot be —S—. In someembodiments, at least one of Q₁, Q₂, and Q₃, is CR₁ or CR₂.

In some embodiments, R₁ and R₂ are each independently H, deuterium,hydroxyl, halogen, cyano, nitro, optionally substituted amino,optionally substituted C-amido, optionally substituted N-amido,optionally substituted urea, optionally substituted ester, optionallysubstituted C₁-C₆ alkoxy, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀aryl, optionally substituted 3 to 10-membered heterocyclyl, optionallysubstituted 5 to 10-membered heteroaryl,

or L-Y. In some embodiments, when one of R₁ or R₂ is

the other of R₁ or R₂ is not L-Y;

In some embodiments, R₅ is H, deuterium, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl.

In some embodiments, X is C(R₅)₂, CH(R₅), CH₂, C═O, or C═S; when Q₃ is—S—, X is C(R₅)₂, CH(R₅) or CH₂.

In some embodiments, X₁ is selected from H, deuterium, hydroxyl,halogen, cyano, nitro, optionally substituted amino, optionallysubstituted C-amido, optionally substituted N-amido, optionallysubstituted ester, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 3to 10-membered heterocyclyl, and optionally substituted 5 to 10-memberedheteroaryl.

In some embodiments, X₁ is selected from H, deuterium, halogen, andoptionally substituted C₁-C₆ alkyl.

In some embodiments, X₂ is selected from (CH₂)_(a), (CF₂)_(a),(CD₂)_(a), C═O, NH, N—(optionally substituted C₁-C₆ alkyl), and[(CH₂)_(p)—O—(CH₂)_(q)]_(r).

In some embodiments, X₃ is selected from O, NH, and S.

In some embodiments, a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, n is 1, 2, or 3. In some embodiments, m is 1, 2, 3, 4, or5. In some embodiments, p and q are independently 0, 1, 2, 3, 4, 5, or6. In some embodiments, r is 0, 1, 2, 3, or 4.

In some embodiments, Qa and Qb are each independently C═O, C═S, or CH₂.In some embodiments, when n is 2, then Q₃ is —S—, or when n is 2, thenR₁ is substituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted 3 to 10-membered heterocyclyl, optionallysubstituted 5 to 10-membered heteroaryl, optionally substituted urea, orL-Y. In some embodiments, when n is 2, then Q₃ is —S—. In someembodiments, when n is 2, then R₁ is substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted 3 to 10-memberedheterocyclyl, optionally substituted 5 to 10-membered heteroaryl, orL-Y. In some embodiments, when n is 2 and Q₁ is —S—, then one of R₁ orR₂ is

optionally substituted urea, or L-Y. In some embodiments, when n is 2and Q₁ is —S—, then one of R₁ or R₂ is

In some embodiments, when n is 2 and Q₁ is —S—, then one of R₁ or R₂ is

In some embodiments, when n is 2 and Q₁ is —S—, then one of R₁ or R₂ isL-Y. In some embodiments, wherein n is 2 and Q₂ is —S—, then one of R₁or R₂ is

optionally substituted urea, or L-Y. In some embodiments, when n is 2and Q₂ is —S—, then one of R₁ or R₂ is

In some embodiments, when n is 2 and Q₂ is —S—, then one of R₁ or R₂ is

In some embodiments, when n is 2 and Q₂ is —S—, then one of R₁ or R₂ isL-Y. In some embodiments, when n is 2 and Q₂ is —S—, then one of R₁ orR₂ is optionally substituted urea.

In some embodiments, L is —Z₁—(R₆—O—R₆)_(t)—Z₂—; —Z₁(R₆—NH—R₆)_(t)—Z₂—;—Z₁—(R₆—S—R₆)_(t)—Z₂—; —Z₁—(R₆—(C═O)—R₆)_(t)—Z₂—;—Z₁—(R₆—(CO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—(NHCO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(CONH)—R₆)_(t)—Z₂—; Z₁—(R₆—(SO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(SO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═NH)NH—R₆)_(t)—Z₂—;—Z₁—(R₆—(NHSO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—(SO₂NH)—R₆)_(t)—Z₂—; or—Z₁—(R₆-R₇—R₆)_(t)—Z₂—. In some embodiments, each t is independently 1,2, 3, 4, 5, 6, 7, or 8.

In some embodiments, L is —Z₁—(R₆—O—R₆)_(t)—Z₂—; —Z₁(R₆—NH—R₆)_(t)—Z₂—;—Z₁—(R₆—S—R₆)_(t)—Z₂—; —Z₁—(R₆—(C═O)—R₆)_(t)—Z₂—;—Z₁—(R₆—(CO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—(NHCO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(CONH)—R₆)_(t)—Z₂—; —Z₁—(R₆—(SO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(SO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—(NHSO₂)—R₆)_(t)—Z₂—;—Z₁—(R₆—(SO₂NH)—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═O)NH—R₆)_(t)—Z₂—;—Z₁—(R₆—NH(C═NH)NH—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═S)NH—R₆)_(t)—Z₂—; or—Z₁—(R₆-R₇—R₆)_(t)—Z₂—. In some embodiments, each t is independently 1,2, 3, 4, 5, 6, 7, or 8.

In some embodiments, Z₁ and Z₂ are each independently —CH₂—; —O—; —S—;S═O; —SO₂—; C═O; —CO₂—; —NH—; —NH(CO)—; —(CO)NH—; —NH—SO₂—; —SO₂—NH—;—R₆CH₂—; —R₆O—; —R₆S—; R₆—S═O; —R₆SO₂—; R₆—C═O; —R₆CO₂—; —R₆NH—;—R₆NH(CO)—; —R₆(CO)NH—; —R₆NH—SO₂—; —R₆SO₂—NH—; —CH₂R₆—; —OR₆—; —SR₆—;—S═O—R₆; —SO₂R₆—; —C═O—R₆; —CO₂R₆—; —NHR₆—; —NH(CO)R₆—; —(CO)NHR₆—;—NH—SO₂R₆—; or —SO₂—NHR₆—.

In some embodiments, each R₆ is absent, or independently C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl, 3 to 10-memberedheterocyclyl, or 5 to 10-membered heteroaryl. In some embodiments, R₇ isoptionally substituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀aryl, optionally substituted 3 to 10-membered heterocyclyl, oroptionally substituted 5 to 10-membered heteroaryl. In some embodiments,R₈ is selected from optionally substituted C₃-C₁₀ cycloalkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 5 to 10-memberedheteroaryl, optionally substituted 3 to 10-membered heterocyclyl,optionally substituted C₁-C₁₀ alkyl, R_(8A), and R_(8B). In someembodiments, R_(8A) is selected from hydroxyl, halogen, cyano, nitro,unsubstituted amino, mono-substituted amino, di-substituted amino,optionally substituted C-amido, optionally substituted N-amido,optionally substituted ester, optionally substituted sulfonyl,optionally substituted S-sulfonamido, optionally substitutedN-sulfonamido, optionally substituted sulfonate, optionally substitutedO-thiocarbamyl, optionally substituted N-thiocarbamyl, optionallysubstituted N-carbamyl, optionally substituted O-carbamyl, optionallysubstituted urea, optionally substituted thiourea, optionallysubstituted C₁-C₆ alkoxy, optionally substituted C₁-C₆ haloalkoxy,optionally substituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl), optionallysubstituted C₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted 5 to 10membered heteroaryl(C₁-C₆ alkyl), and optionally substituted 3 to 10membered heterocyclyl(C₁-C₆ alkyl). In some embodiments, R_(8A) isselected from optionally substituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl),optionally substituted C₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted5 to 10 membered heteroaryl(C₁-C₆ alkyl), and optionally substituted 3to 10 membered heterocyclyl(C₁-C₆ alkyl). In some embodiments, R_(8B) isY₁.

In some embodiments, Y is

wherein Y is derivatized to attach to L.

In some embodiments, Y₁ is

wherein Y₁ is derivatized to attach to X₂.

In some embodiments,

represents a carbon-carbon single bond, a carbon-carbon double bond, ora carbon-sulfur single bond. It is understood that the combinations ofdouble and/or single bonds generated by

do not exceed atomic valence requirements. It is also understood thatany resulting open valences are filled by hydrogen, deuterium, or aresubstituted as set forth herein.

In some embodiments, the compound of Formula (II) is selected fromcompounds of Formula (IIa)

Formula (IIb)

and Formula (IIc)

or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula (II) is a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is a compound ofFormula (IIb):

or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula (II) is a compound of Formula (IIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is selected fromcompounds of Formula (IId)

Formula (IIe)

and Formula (IIf)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is a compound ofFormula (IId):

or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula (II) is a compound of Formula (IIe):

or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula (II) is a compound of Formula (IIf):

or a pharmaceutically acceptable salt thereof.

In some embodiments, Qa is C═O and Qb is C═O or CH₂. In someembodiments, Qa is C═O and Qb is C═O. In some embodiments, Qa is C═O andQb is CH₂. In some embodiments, Qa is C═S and Qb is C═O, CH₂ or C═S.

In some embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3.

In some embodiments, R₅ is H. In some embodiments, R₅ is optionallysubstituted C₁-C₆ alkyl.

In some embodiments, X is CH₂. In some embodiments, X is C═O.

In some embodiments, X₁ is selected from H, deuterium, halogen, andoptionally substituted C₁-C₆ alkyl. In some embodiments, X₁ is selectedfrom H and fluoro. In some embodiments, X₁ is an unsubstituted C₁-C₆alkyl.

In some embodiments, R₁ is optionally substituted C₁-C₆ alkyl. In someembodiments, R₂ is optionally substituted C₁-C₆ alkyl. In someembodiments, R₁ and R₂ are each independently optionally substitutedC₁-C₆ alkyl.

In some embodiments, L is —Z₁—(R₆—O—R₆)_(t)—Z₂—; —Z₁(R₆—NH—R₆)_(t)—Z₂—;—Z₁—(R₆—(NHCO)—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═O)NH—R₆)_(t)—Z₂—;—Z₁—(R₆—NH(C═S)NH—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═NH)NH—R₆)_(t)—Z₂—; or—Z₁—(R₆—(CONH)—R₆)_(t)—Z₂—. In some embodiments, t is 1, 2, 3, or 4. Insome embodiments, Z₁ and Z₂ are each independently —CH₂—; —O—; —NH—;—NH(CO)—; or —(CO)NH.

In some embodiments, R₁ is

In some embodiments, R² is

In some embodiments, R¹ is

In some embodiments, R² is

In some embodiments, one of R₁ and R₂ is an optionally substituted urea,and the other of R₁ and R₂ is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. Insome embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, X₃ is O. In some embodiments, X₃ is NH. In someembodiments, X₃ is S.

In some embodiments, X₂ is selected from (CH₂)_(a), C═O, and[(CH₂)_(p)—O—(CH₂)_(q)]_(t). In some embodiments, X₂ is (CH₂)_(a).

In some embodiments, a is 0, 1, 2, or 3. In some embodiments, a is 0. Insome embodiments, a is 1. In some embodiments, a is 2. In someembodiments, a is 3.

In some embodiments, p and q are independently 0, 1, 2, or 3. In someembodiments, p and q are independently 2 or 3. In some embodiments, pand q are independently 0, 1, or 2. In some embodiments, p and q areindependently 1 or 2.

In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 1. Insome embodiments, t is 2. In some embodiments, t is 3.

In some embodiments, X₂ is NH or N—(an optionally substituted C₁-C₆alkyl). In some embodiments, X₂ is NH.

In some embodiments, R₈ is selected from an optionally substitutedC₃-C₁₀ cycloalkyl, an optionally substituted C₆-C₁₀ aryl, an optionallysubstituted 5 to 10-membered heteroaryl, and an optionally substituted 3to 10-membered heterocyclyl. In some embodiments, the optionallysubstituted C₆-C₁₀ aryl is a mono-substituted phenyl group. In someembodiments, the optionally substituted C₆-C₁₀ aryl is a di-substitutedphenyl group. In some embodiments, the optionally substituted C₆-C₁₀aryl is a tri-substituted phenyl group. In some embodiments, theoptionally substituted C₆-C₁₀ aryl is a phenyl group substituted withhalogen. In some embodiments, the optionally substituted C₆-C₁₀ aryl isa phenyl group substituted with an unsubstituted C₁-C₆ alkyl. In someembodiments, the optionally substituted C₆-C₁₀ aryl is a phenyl groupsubstituted with an unsubstituted C₁-C₆ alkyl and a halogen.

In some embodiments, R_(8A) is selected from hydroxyl, halogen, cyano,nitro, unsubstituted amino, mono-substituted amino, di-substitutedamino, optionally substituted C-amido, optionally substituted N-amido,optionally substituted ester, optionally substituted sulfonyl,optionally substituted S-sulfonamido, optionally substitutedN-sulfonamido, optionally substituted sulfonate, optionally substitutedO-thiocarbamyl, optionally substituted N-thiocarbamyl, optionallysubstituted N-carbamyl, optionally substituted O-carbamyl, optionallysubstituted urea, optionally substituted thiourea, optionallysubstituted C₁-C₆ alkoxy, optionally substituted C₁-C₆ haloalkoxy,optionally substituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl), optionallysubstituted C₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted 5 to 10membered heteroaryl(C₁-C₆ alkyl), and optionally substituted 3 to 10membered heterocyclyl(C₁-C₆ alkyl). In some embodiments, R_(8A) isselected from optionally substituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl),optionally substituted C₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted5 to 10 membered heteroaryl(C₁-C₆ alkyl), and optionally substituted 3to 10 membered heterocyclyl(C₁-C₆ alkyl). In some embodiments, R₈ isR_(8B) and R_(8B) is Y₁.

In some embodiments, the optionally substituted C₆-C₁₀ aryl is a phenylgroup substituted with an unsubstituted C₁-C₆ alkyl and halogen. In someembodiments, the optionally substituted 5 to 10-membered heteroaryl is 5or 6-membered heteroaryl substituted with halogen. In some embodiments,the optionally substituted 5 to 10-membered heteroaryl is 5 or6-membered heteroaryl substituted with an unsubstituted C₁-C₆ alkyl. Insome embodiments, the optionally substituted 5 to 10-membered heteroarylis 5 or 6-membered heteroaryl substituted with an unsubstituted C₁-C₆alkyl and halogen. In some embodiments, the optionally substitutedC₆-C₁₀ aryl is a phenyl group substituted with an optionally substituted3 to 10-membered heterocyclyl. In some embodiments, the optionallysubstituted 3 to 10-membered heterocyclyl is an unsubstituted 5 to7-membered heterocyclyl group. In some embodiments, the unsubstituted 5to 7-membered heterocyclyl group is pyrrolidinyl, morpholino,piperidinyl, piperazinyl, or azepanyl. In some embodiments, theoptionally substituted 5 to 10-membered heteroaryl is 5 or 6-memberedheteroaryl substituted with an optionally substituted 3 to 10-memberedheterocyclyl. In some embodiments, the optionally substituted 3 to10-membered heterocyclyl is an unsubstituted 5 to 7-memberedheterocyclyl group. In some embodiments, the unsubstituted 5 to7-membered heterocyclyl group is pyrrolidinyl, morpholino, piperidinyl,piperazinyl, or azepanyl.

In some embodiments, the compound of Formula (II) is selected from:

or a pharmaceutically acceptable salt or solvates of any of theforegoing.

In some embodiments, the compound of Formula (II) is selected from:

or a pharmaceutically acceptable salt or solvates of any of theforegoing. In some embodiments, the compound is a pharmaceuticallyacceptable salt.

Some embodiments provide a pharmaceutical composition comprising acompound of any one of Formula (II), (IIa), (IIb), (IIc), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In some embodiments, thecomposition is formulated for oral, parenteral, topical, ophthalmic,inhalation, nasal, or intravenous administration.

In some embodiments, the pharmaceutical composition further comprises asecond therapeutic agent. In some embodiments, the second therapeuticagent is selected from anti-inflammatory agents, anti-cancer agents,immunostimulatory agents, and immunosuppressive agents. In someembodiments, the second therapeutic agent is an anti-cancer agent.

Some embodiments provide a method of treating, ameliorating, orpreventing a disease, disorder, or condition associated with a proteinselected from a cytokine, aiolos, ikaros, helios, CK1α, GSPT1, andcombinations of any of the foregoing, the method comprisingadministering a therapeutically effective amount of a compound of anyone of Formula (II), (IIa), (IIb), (IIc), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprisingFormula (II), (IIa), (IIb), (IIc), or a pharmaceutically acceptable saltthereof.

In some embodiments, the disease, disorder, or condition is selectedfrom inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease,Alzheimer's disease, and cancer.

In some embodiments, the disease, disorder, or condition is cancer.Examples of suitable cancers include, but are not limited tohematological malignancies and solid tumors, such as: lung cancers(e.g., small cell lung cancer and non-small cell lung cancer), breastcancers, prostate cancers, head and neck cancers (e.g., squamous cellcancer of the head and neck), pancreatic cancers (e.g., pancreaticcarcinoma such as, for example, exocrine pancreatic carcinoma, ormoderately differentiated metastatic pancreatic neuroendocrine tumors(pNETs)), colon cancers (e.g., colorectal carcinomas, such as, forexample, colon adenocarcinoma and colon adenoma), rectal cancers,teratomas, ovarian cancers, endometrial cancers, brain cancers (e.g.,recurrent, progressive, or refractory CNS tumors; gliomas, such asglioma blastoma multiforme and oligodendroglioma; astrocytomas; orprogressive brain metastases), retinoblastoma, leukemias (e.g.,MLL-rearranged acute leukemia or acute lymphoblastic leukemia), skincancers (e.g., melanoma or squamous cell carcinoma), liposarcomas,lymphomas (e.g, mantle cell lymphoma), multiple myelomas, testicularcancers, liver cancers (e.g., hepatocellular carcinoma), esophagealcancers, kidney carcinomas, astrogliosis, and neuroblastoma.

In some embodiments, the compound of Formula (II) is administered incombination with a second therapeutic agent. In some embodiments, thesecond therapeutic agent is selected from anti-inflammatory agents,anti-cancer agents, immunostimulatory agents, and immunosuppressiveagents. In some embodiments, the second therapeutic agent is ananti-cancer agent.

Some embodiments provide a method of inhibiting protein activity,comprising contacting a cell with a compound of any of Formula (II),(IIa), (IIb), (IIc), or a pharmaceutically acceptable salt thereof,wherein the protein is aiolos, ikaros, helios, CK1α, GSPT1, a cytokine,or a combination of any of the foregoing.

Some embodiments provide a method of decreasing the risk of skin cancerin a subject in need thereof, comprising administering an effectiveamount of a compound of any of Formula (II), (IIa), (IIb), (IIc), or apharmaceutically acceptable salt thereof, or a composition comprisingFormula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), or apharmaceutically acceptable salt thereof.

Some embodiments provide a method for treating, ameliorating, orpreventing a skin disorder, disease, or condition in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of any of Formula (II), (IIa), (IIb), (IIc), or apharmaceutically acceptable salt thereof, or a composition comprisingFormula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), or apharmaceutically acceptable salt thereof.

In some embodiments, the skin disorder, disease, or condition is sunburnor skin hypopigmentation.

Some embodiments provide a method for treating, ameliorating, orpreventing a skin disorder, disease, or condition in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of any of Formula (II), (IIa), (IIb), (IIc), or apharmaceutically acceptable salt thereof, or a composition comprisingFormula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), or apharmaceutically acceptable salt thereof.

Some embodiments provide a method of increasing skin pigmentation in asubject in need thereof, comprising administering a therapeuticallyeffective amount of any of (Formula (II), (IIa), (IIb), (IIc), (IId),(IIe), (IIf), or a pharmaceutically acceptable salt thereof, or acomposition comprising Formula (II), (IIa), (IIb), (IIc), (IId), (IIe)or (IIf), or a pharmaceutically acceptable salt thereof.

In some embodiments, administering comprising contacting the skin with atherapeutically effective amount of any of Formula (II), (IIa), (IIb),(IIc), (IId), (IIe), (IIf), or a pharmaceutically acceptable saltthereof, or a composition comprising Formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf), or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of increasing eumelanin level in asubject in need thereof, comprising administering a therapeuticallyeffective amount of any of Formula (II), (IIa), (IIb), (IIc), (IId),(IIe) or (IIf), or a pharmaceutically acceptable salt thereof, or acomposition comprising Formula (II), (IIa), (IIb), (IIc), (IId), (IIe)or (IIf), or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of increasing p53 activity, comprisingcontacting a cell with a compound of any of (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf), or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of decreasing MDM2 activity,comprising contacting a cell with a compound of any of (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf), or a pharmaceutically acceptablesalt thereof.

Any of the features of an embodiment is applicable to all embodimentsidentified herein. Moreover, any of the features of an embodiment isindependently combinable, partly or wholly with other embodimentsdescribed herein in any way, e.g., one, two, or three or moreembodiments may be combinable in whole or in part. Further, any of thefeatures of an embodiment may be made optional to other embodiments. Anyembodiment of a method can comprise another embodiment of a compound,and any embodiment of a compound can be configured to perform a methodof another embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing IL-1-beta expression in LPS stimulated CD14+monocytes. CD14+ monocytes were plated in 96-well plates and pretreatedwith compound (10 μM Compound 2 or 10 μm lenalidomide (rev)) for 1 h,and then induced with 100 ng/mL LPS for 18-24 h. Cytokines were measuredaccording to MesoScale protocol. Negative control wells were treatedwith DMSO. Compound activity was measured as a percentage of LPS-inducedactivity.

FIG. 2 is a graph showing IL-6 expression in LPS stimulated CD14+monocytes. CD14+ monocytes were plated in 96-well plates and pretreatedwith compound (10 μM Compound 2 or 10 μM lenalidomide (rev)) for 1 h,and then induced with 100 ng/mL LPS for 18-24 h. Cytokines were measuredaccording to MesoScale protocol. Negative control wells were treatedwith DMSO. Compound activity was measured as a percentage of LPS-inducedactivity.

FIG. 3 is a graph showing TNF-α expression in LPS stimulated CD14+monocytes. CD14+ monocytes were plated in 96-well plates and pretreatedwith compound (10 μM Compound 2 or 10 μM lenalidomide (rev)) for 1 h,and then induced with 100 ng/mL LPS for 18-24 h. Cytokines were measuredaccording to MesoScale protocol. The negative control wells were treatedwith DMSO. Compound activity was measured as a percentage of LPS-inducedactivity.

FIGS. 4 and 9D are graphs showing anti-CD3-induced IL-2 secretion inPBMCs. 1 ug/mL anti-CD3 (OKT-3) antibody in PBS were coated onto 96-wellplates overnight at 4° C. Approximately 550,000 PBMCs were added to eachwell, followed by addition of DMSO only, Compound 1-8 at 10 μM (FIG. 4)or Compound 9 at 0.1 μM or 1 μM (FIG. 9D), or 10 μM lenalidomide (rev).Induction was measured after 24 h as fold difference from the DMSOstimulated control.

FIGS. 5 and 9A are graphs showing IL-1-beta expression in LPS stimulatedperipheral blood mononuclear cells (PBMCs). PBMCs were plated in 96-wellplates and pretreated with compound (Compound 1-9 individually) for 1 h,and then induced with 100 ng/mL LPS for 18-24 h. Cytokines in the mediawere measured according to MesoScale protocol. Negative control wellswere treated with DMSO. Compound activity is measured as a percentage ofLPS-induced activity. “Rev” is lenalidomide.

FIGS. 6 and 9B are graphs showing IL-6 expression in LPS stimulatedperipheral blood mononuclear cells (PBMCs). PBMCs were plated in 96-wellplates and pretreated with compound (Compound 1-9 individually) for 1 h,and then induced with 100 ng/mL LPS for 18-24 h. Cytokines were measuredaccording to MesoScale protocol. Negative control wells were treatedwith DMSO. Compound activity was measured as a percentage of LPS-inducedactivity. “Rev” is lenalidomide.

FIGS. 7 and 9C are graphs showing TNF-α expression in LPS stimulatedperipheral blood mononuclear cells (PBMCs). PBMCs were plated in 96-wellplates and pretreated with compound (Compound 1-9 individually) for 1 h,and then induced with 100 ng/mL LPS for 18-24 h. Cytokines in the mediawere measured according to MesoScale protocol. The negative controlwells were treated with DMSO. Compound activity is measured as apercentage of LPS-induced activity. “Rev” is lenalidomide.

FIG. 8A shows the results of a Western Blot analysis of Jurkat cellstreated with Control (DMSO only), or 10 μM compound (Compound 1, 2, 4,5, 7, and 8) or lenalidomide (Rev). Cells were lysed using RIPA Buffer(Pierce) and a Western Blot analysis was performed using anti-ikaros,anti-CK1α, and anti-β-actin antibodies. FIG. 8B is a graph showing theexpression of ikaros protein in Jurkat cells after being treated withDMSO, compound, or Rev. and FIG. 8C is a graph showing the expression ofCK1α protein in Jurkat cells after being treated with DMSO, compound, orRev. Protein expression levels were measured using the LiCor Odysseyinstrumentation and methods.

FIG. 10A is a graph showing antiproliferative activity in H1048 (SCLC)cells. FIG. 10B is a graph showing antiproliferative activity in Molm-13(AML) cells. In FIGS. 10A and 10B, the cells were incubated for 72 hrswith Compound 9 at the indicated concentrations or DMSO. Compoundactivity was measured based on the signal from remaining viable cells.

FIG. 11A shows the result of a Western Blot analysis of Molm-13 cellstreated with Control (DMSO only), or the indicated concentration ofCompound 9. Cells were lysed using RIPA Buffer (Pierce) and a WesternBlot analysis was performed using anti-GSPT1 and anti-β-actinantibodies. FIG. 11B is a graph showing the expression levels of GSPT1protein in Molm-13 (AML) cells. Protein expression levels were measuredusing the LiCor Odyssey instrumentation and methods.

DETAILED DESCRIPTION

Some embodiments provide a compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, compounds of Formula (II) are selected fromcompounds of Formula (IIa), Formula (IIb), or Formula (IIc):

In some embodiments, Q₁, Q₂, and Q₃, are each independently selectedfrom CR₁, CR₂, and —S—, with the proviso that no more than one of Q₁,Q₂, and Q₃, can be —S—. In some embodiments, at least one of Q₁, Q₂, andQ₃, is CR₁ or CR₂.

In some embodiments, Q₁ is CR₁. In some embodiments, Q₁ is CR₂. In someembodiments, Q₁ is —S—. In some embodiments, Q₂ is CR₁. In someembodiments, Q₂ is CR₂. In some embodiments, Q₂ is —S—. In someembodiments, Q₃ is CR₁. In some embodiments, Q₃ is CR₂. In someembodiments, Q₃ is —S—. In some embodiments, Q₁ is CR₁, Q₂ is CR₂, andQ₃ is —S—. In some embodiments, Q₁ is CR₂, Q₂ is CR₁, and Q₃ is —S—.

In some embodiments, Q₁ is —S—, Q₂ is CR₁, and Q₃ is CR₂. In someembodiments, Q₁ is —S—, Q₂ is CR₂, and Q₃ is CR₁. In some embodiments,Q₁ is CR₁, Q₂ is —S—, and Q₃ is CR₂. In some embodiments, Q₁ is CR₂, Q₂is —S—, and Q₃ is CR₁. In some embodiments, Q₁ is CR₁, Q₂ is CR₁, and Q₃is CR₁. In some embodiments, Q₁ is CR₁, Q₂ is CR₂, and Q₃ is CR₁. Insome embodiments, Q₁ is CR₁, Q₂ is CR₂, and Q₃ is CR₂. In someembodiments, Q₁ is CR₂, Q₂ is CR₂, and Q₃ is CR₁. In some embodiments,Q₁ is CR₂, Q₂ is CR₁, and Q₃ is CR₁. In some embodiments, Q₁ is CR₂, Q₂is CR₁, and Q₃ is CR₂. In some embodiments, Q₁ is CR₂, Q₂ is CR₂, and Q₃is CR₂.

In some embodiments, R₁ and R₂ are each independently selected from H,deuterium, hydroxyl, halogen (for example, fluoro, chloro, bromo, andiodo), cyano, nitro, optionally substituted amino, optionallysubstituted C-amido, optionally substituted N-amido, optionallysubstituted urea, optionally substituted ester, optionally substitutedC₁-C₆ alkoxy, optionally substituted C₁-C₆ alkyl (for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl(branched and straight-chained), and hexyl (branched andstraight-chained)), optionally substituted C₂-C₆ alkenyl (for example,vinyl, allyl, isopropenyl, n-butenyl, isobutenyl, pentenyl (branched andstraight-chained), and hexenyl (branched and straight-chained)),optionally substituted C₂-C₆ alkynyl (for example, ethynyl, propynyl,butynyl, pentynyl (branched and straight-chained), and hexynyl (branchedand straight-chained)), optionally substituted C₃-C₈ cycloalkyl (forexample, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, andcyclooctyl), optionally substituted C₆-C₁₀ aryl (for example, phenyl andnaphthyl), optionally substituted 3 to 10-membered heterocyclyl (forexample, monocyclic and bicyclic (including fused, bridged, and spiro) 3to 10 membered heterocyclyl groups with one nitrogen atom, two nitrogenatoms, three nitrogen atoms, four nitrogen atoms, one oxygen atom, onesulfur atom, one oxygen atom and one or two nitrogen atoms, and onesulfur atom and one or two nitrogen atoms), optionally substituted 5 to10-membered heteroaryl (for example, monocyclic and bicyclic 3 to 10membered heteroaryl groups with one nitrogen atom, two nitrogen atoms,three nitrogen atoms, four nitrogen atoms, one oxygen atom, one sulfuratom, one oxygen atom and one or two nitrogen atoms, and one sulfur atomand one or two nitrogen atoms),

and L-Y. In some embodiments, when one of R₁ or R₂ is

the other of R₁ or R₂ is not L-Y.

In some embodiments, R₁ and R₂ are each independently selected from H,deuterium, hydroxyl, halogen, cyano, nitro, unsubstituted amino,unsubstituted C-amido, unsubstituted N-amido, unsubstituted ester,unsubstituted C₁-C₆ alkoxy, unsubstituted C₁-C₆ alkyl, unsubstitutedC₂-C₆ alkenyl, unsubstituted C₂-C₆ alkynyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted C₆-C₁₀ aryl, unsubstituted 3 to 10-memberedheterocyclyl, unsubstituted 5 to 10-membered heteroaryl,

In some embodiments, R₁ is hydrogen and R₂ is L-Y. In some embodiments,R₁ is L-Y and R₂ is H. In some embodiments, R₁ and R₂ are each L-Y. Insome embodiments, none of R₁ or R₂ is L-Y.

In some embodiments, R₁ is

In some embodiments, R₂ is

In some embodiments, R₁ is

In some embodiments, R₁ is

In some embodiments, R₂ is

In some embodiments, R₂ is

For example, in some embodiments, one of R₁ and R₂ is selected from:

In some embodiments of this paragraph, a is 0. In some embodiments ofthis paragraph, a is 1. In some embodiments of this paragraph, a is 2.In some embodiments of this paragraph, a is 3. In some embodiments ofthis paragraph, a is 4. In some embodiments of this paragraph, a is 5.In some embodiments of this paragraph, m is 1. In some embodiments ofthis paragraph, m is 2. In some embodiments of this paragraph, m is 3.In some embodiments of this paragraph, m is 4. In some embodiments ofthis paragraph, m is 5. In some embodiments of this paragraph, p and qare independently 1 or 2. In some embodiments of this paragraph, r is 1.In some embodiments of this paragraph, r is 2. In some embodiments ofthis paragraph, r is 3.

In some embodiments, R₁ and R₂ are each H. In some embodiments, none ofR₁ and R₂ are H. In some embodiments, R₁ and R₂ are each deuterium. Insome embodiments, none of R₁ and R₂ are deuterium. In some embodiments,R₁ and R₂ are each halogen. In some embodiments, none of R₁ and R₂ arehalogen.

In some embodiments, R₁ is optionally substituted amino. In someembodiments, R₁ is unsubstituted amino. In some embodiments, R₁ isnitro. In some embodiments, R₁ is optionally substituted C₁-C₆ alkoxy.In some embodiments, R₁ is unsubstituted C₁-C₆ alkoxy.

In some embodiments, R₁ is halogen. In some embodiments, R₁ is cyano. Insome embodiments, R₁ is optionally substituted amido. In someembodiments, R₁ is optionally substituted ester.

In some embodiments, R₁ is optionally substituted C₁-C₆ alkyl. In someembodiments, R₁ is optionally substituted C₂-C₆ alkenyl. In someembodiments, R₁ is optionally substituted C₂-C₆ alkynyl. In someembodiments, R₁ is optionally substituted C₃-C₈ cycloalkyl. In someembodiments, R₁ is optionally substituted C₆-C₁₀ aryl. In someembodiments, R₁ is optionally substituted 3 to 10-membered heterocyclyl.In some embodiments, R₁ is optionally substituted 5 to 10-memberedheteroaryl.

In some embodiments, R₁ is unsubstituted amido. In some embodiments, R₁is unsubstituted ester.

In some embodiments, R₁ is unsubstituted C₁-C₆ alkoxy. In someembodiments, R₁ is unsubstituted C₁-C₆ alkyl. In some embodiments, R₁ isunsubstituted C₂-C₆ alkenyl. In some embodiments, R₁ is hydroxyl.

In some embodiments, R₁ is unsubstituted C₂-C₆ alkynyl. In someembodiments, R₁ is unsubstituted C₃-C₈ cycloalkyl. In some embodiments,R₁ is unsubstituted C₆-C₁₀ aryl. In some embodiments, R₁ isunsubstituted 3 to 10-membered heterocyclyl. In some embodiments, R₁ isunsubstituted 5 to 10-membered heteroaryl.

In some embodiments, R₂ is optionally substituted amino. In someembodiments, R₂ is unsubstituted amino. In some embodiments, R₂ isnitro. In some embodiments, R₂ is optionally substituted C₁-C₆ alkoxy.In some embodiments, R₂ is unsubstituted C₁-C₆ alkoxy.

In some embodiments, R₂ is halogen. In some embodiments, R₂ is cyano. Insome embodiments, R₂ is optionally substituted amido. In someembodiments, R₂ is optionally substituted ester.

In some embodiments, R₂ is optionally substituted C₁-C₆ alkyl. In someembodiments, R₂ is optionally substituted C₂-C₆ alkenyl. In someembodiments, R₂ is optionally substituted C₂-C₆ alkynyl. In someembodiments, R₂ is optionally substituted C₃-C₈ cycloalkyl. In someembodiments, R₂ is optionally substituted C₆-C₁₀ aryl. In someembodiments, R₂ is optionally substituted 3 to 10-membered heterocyclyl.In some embodiments, R₂ is optionally substituted 5 to 10-memberedheteroaryl.

In some embodiments, R₂ is unsubstituted amido. In some embodiments, R₂is unsubstituted ester. In some embodiments, R₂ is unsubstituted C₁-C₆alkoxy.

In some embodiments, R₂ is unsubstituted C₁-C₆ alkyl. In someembodiments, R₂ is unsubstituted C₂-C₆ alkenyl. In some embodiments, R₂is unsubstituted C₂-C₆ alkynyl. In some embodiments, R₂ is unsubstitutedC₃-C₈ cycloalkyl. In some embodiments, R₂ is unsubstituted C₆-C₁₀ aryl.In some embodiments, R₂ is unsubstituted 3 to 10-membered heterocyclyl.In some embodiments, R₂ is unsubstituted 5 to 10-membered heteroaryl.

In some embodiments, R₁ is hydrogen, and R₂ is optionally substitutedC₁-C₆ alkyl. In some embodiments, R₁ is hydrogen, and R₂ isunsubstituted C₁-C₆ alkyl. In some embodiments, R₁ is optionallysubstituted C₁-C₆ alkyl, and R₂ is hydrogen. In some embodiments, R₁ isunsubstituted C₁-C₆ alkyl, and R₂ is hydrogen. In some embodiments, R₁is hydrogen and R₂ is optionally substituted methyl. In someembodiments, R₁ is hydrogen and R₂ is unsubstituted methyl. In someembodiments, R₁ is optionally substituted methyl and R₂ is hydrogen. Insome embodiments, R₁ is unsubstituted methyl and R₂ is hydrogen.

In some embodiments, X₁ is selected from H, deuterium, halogen, andoptionally substituted C₁-C₆ alkyl.

In some embodiments, X₁ is hydrogen. In some embodiments, X₁ isdeuterium. In some embodiments, X₁ is halogen, for example, chloro orfluoro.

In some embodiments, X₁ is optionally substituted C₁-C₆ alkyl. In someembodiments, X₁ is substituted C₁-C₆ alkyl. In some embodiments, X₁ isunsubstituted C₁-C₆ alkyl.

In some embodiments, X₁ is not hydrogen. In some embodiments, X₁ is notdeuterium. In some embodiments, X₁ is not optionally substituted C₁-C₆alkyl. In some embodiments, X₁ is not unsubstituted C₁-C₆ alkyl. In someembodiments, X₁ is not optionally substituted methyl. In someembodiments, X₁ is not unsubstituted methyl.

In some embodiments, R₅ is selected from H, deuterium, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, and optionally substituted C₃-C₈cycloalkyl.

In some embodiments, R₅ is selected from H, deuterium, unsubstitutedC₁-C₆ alkyl, unsubstituted C₂-C₆ alkenyl, unsubstituted C₂-C₆ alkynyl,and unsubstituted C₃-C₈ cycloalkyl.

In some embodiments, X is selected from C(R₅)₂, CH(R₅), CH₂, C═O, andC═S.

In some embodiments, X₂ is selected from (CH₂)_(a), (CD₂)_(a),(CF₂)_(a), C═O, NH, N—(an optionally substituted C₁-C₆ alkyl), and[(CH₂)_(p)—O—(CH₂)_(q)]_(t). In some embodiments, X₂ is NH or N—(anoptionally substituted C₁-C₆ alkyl). In some embodiments, X₂ is NH. Insome embodiments, X₂ is (CH₂)_(a). In some embodiments, X₂ is (CD2)_(a).In some embodiments, X₂ is C═O. In some embodiments, X₂ is NH. In someembodiments, X₂ is N—(an optionally substituted C₁-C₆ alkyl). In someembodiments, X₂ is [(CH₂)_(p)—O—(CH₂)_(q)]_(t).

In some embodiments, X₃ is selected from O, NH, and S. In someembodiments, X₃ is O. In some embodiments, X₃ is NH. In someembodiments, X₃ is S.

In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1.In some embodiments, m is 2. In some embodiments, m is 3. In someembodiments, m is 4. In some embodiments, m is 5. In some embodiments, mis 1 and X₂ is NH.

In some embodiments, each Qa and Qb are each independently selected fromC(R₅)₂, CH(R₅), CH₂, C═O, and C═S.

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. Insome embodiments, n is 2. In some embodiments, n is 3. In someembodiments, when n is 2, then Q₃ is —S—, or when n is 2, then R₁ issubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted 3 to 10-membered heterocyclyl, optionallysubstituted 5 to 10-membered heteroaryl, optionally substituted urea, orL-Y. In some embodiments, when n is 2, then Q₃ is —S—. In someembodiments, when n is 2, then R₁ is substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted 3 to 10-memberedheterocyclyl, optionally substituted 5 to 10-membered heteroaryl,optionally substituted urea, or L-Y.

In some embodiments, Qa and Qb are each independently selected from CH₂and C═O. In some embodiments, Qa and Qb are each CH₂. In someembodiments, Qa and Qb are each C═O. In some embodiments, Qa is CH₂ andQb is C═O. In some embodiments, Qb is CH₂ and Qa is C═O.

In some embodiments, R₅ is H. In some embodiments, R₅ is optionallysubstituted C₁-C₆ alkyl.

In some embodiments, L is a linker group. In some embodiments, L is analkyl linker. In some embodiments, L is a polyethylene glycol(PEG)-based linker. L is connected to Y such that Y maintains bindingaffinity for its target(s), as discussed herein.

In some embodiments, L is —Z₁—(R₆—O—R₆)_(t)—Z₂—; —Z₁(R₆—NH—R₆)_(t)—Z₂—;—Z₁—(R₆—S—R₆)_(t)—Z₂—; —Z₁—(R₆—(C═O)—R₆)_(t)—Z₂—;—Z₁—(R₆—(CO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—(NHCO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(CONH)—R₆)_(t)—Z₂—; —Z₁—(R₆—(SO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(SO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—(NHSO₂)—R₆)_(t)—Z₂—;—Z₁—(R₆—(SO₂NH)—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═O)NH—R₆)_(t)—Z₂—;—Z₁—(R₆—NH(C═NH)NH—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═S)NH—R₆)_(t)—Z₂—; or—Z₁—(R₆-R₇—R₆)_(t)—Z₂—.

In some embodiments, each t is independently 1, 2, 3, 4, 5, 6, 7, or 8.In some embodiments, t is 0. In some embodiments, t is 1. In someembodiments, t is 2. In some embodiments, t is 3. In some embodiments, tis 4. In some embodiments, t is 5. In some embodiments, t is 6. In someembodiments, t is 7. In some embodiments, t is 8.

In some embodiments, p and q are independently 0, 1, 2, 3, 4, 5, or 6.In some embodiments, p and q are independently 0. In some embodiments, pand q are independently 1. In some embodiments, p and q areindependently 2. In some embodiments, p and q are independently 3. Insome embodiments, p and q are independently 4. In some embodiments, pand q are independently 5. In some embodiments, p and q areindependently 6.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2. In some embodiments, p is 3. In some embodiments, pis 4. In some embodiments, p is 5. In some embodiments, p is 6. In someembodiments, q is 0. In some embodiments, q is 1. In some embodiments, qis 2. In some embodiments, q is 3. In some embodiments, q is 4. In someembodiments, q is 5. In some embodiments, q is 6. In some embodiments, pand q are each 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, Z₁ and Z₂ are each independently —CH₂—; —O—; —S—;S═O; —SO₂—; C═O; —CO₂—; —NH—; —NH(CO)—; —(CO)NH—; —NH—SO₂—; —SO₂—NH—;—R₆CH₂—; —R₆O—; —R₆S—; R₆—S═O; —R₆SO₂—; R₆—C═O; —R₆CO₂—; —R₆NH—;—R₆NH(CO)—; —R₆(CO)NH—; —R₆NH—SO₂—; —R₆SO₂—NH—; —CH₂R₆—; —OR₆—; —SR₆—;S═O—R₆; —SO₂R₆—; C═O—R₆; —CO₂R₆—; —NHR₆—; —NH(CO)R₆—; —(CO)NHR₆—;—NH—SO₂R₆—; or —SO₂—NHR₆—.

In some embodiments, each R₆ is absent, or independently C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl, 3 to 10-memberedheterocyclyl, or 5 to 10-membered heteroaryl.

In some embodiments, R₇ is optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 3 to10-membered heterocyclyl, or optionally substituted 5 to 10-memberedheteroaryl.

In some embodiments, R₈ is selected from an optionally substitutedC₃-C₁₀ cycloalkyl, an optionally substituted C₆-C₁₀ aryl, an optionallysubstituted 5 to 10-membered heteroaryl, and an optionally substituted 3to 10-membered heterocyclyl. In some embodiments, the optionallysubstituted C₆-C₁₀ aryl is an unsubstituted phenyl group. In someembodiments, the optionally substituted C₆-C₁₀ aryl is an unsubstitutednaphthyl group. In some embodiments, the optionally substituted C₆-C₁₀aryl is a phenyl group substituted with halogen. In some embodiments,the optionally substituted C₆-C₁₀ aryl is a phenyl group substitutedwith an unsubstituted C₁-C₆ alkyl. In some embodiments, the optionallysubstituted C₆-C₁₀ aryl is a phenyl group substituted with anunsubstituted C₁-C₆ alkyl and halogen. In some embodiments, theoptionally substituted 5 to 10-membered heteroaryl is 5 or 6-memberedheteroaryl substituted with halogen. In some embodiments, the optionallysubstituted 5 to 10-membered heteroaryl is 5 or 6-membered heteroarylsubstituted with an unsubstituted C₁-C₆ alkyl. In some embodiments, theoptionally substituted 5 to 10-membered heteroaryl is 5 or 6-memberedheteroaryl substituted with an unsubstituted C₁-C₆ alkyl and halogen.

In some embodiments, the optionally substituted C₆-C₁₀ aryl is a phenylgroup substituted with an optionally substituted 3 to 10-memberedheterocyclyl. In some embodiments, the optionally substituted 3 to10-membered heterocyclyl is an unsubstituted 5 to 7-memberedheterocyclyl group. In some embodiments, the unsubstituted 5 to7-membered heterocyclyl group is pyrrolidinyl, morpholino, piperidinyl,piperazinyl, or azepanyl. In some embodiments, the optionallysubstituted 5 to 10-membered heteroaryl is 5 or 6-membered heteroarylsubstituted with an optionally substituted 3 to 10-memberedheterocyclyl. In some embodiments, the optionally substituted 3 to10-membered heterocyclyl is an unsubstituted 5 to 7-memberedheterocyclyl group. In some embodiments, the unsubstituted 5 to7-membered heterocyclyl group is pyrrolidinyl, morpholino, piperidinyl,piperazinyl, or azepanyl.

In some embodiments, R₈ is selected from:

In some embodiments, R₈ is selected from:

In some embodiments, R₈ is selected from:

In some embodiments, R₈ is selected from:

In some embodiments, R₈ is R_(8A) and R_(8A) is selected from optionallysubstituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl), optionally substitutedC₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted 5 to 10 memberedheteroaryl(C₁-C₆ alkyl), and optionally substituted 3 to 10 memberedheterocyclyl(C₁-C₆ alkyl).

In some embodiments, R_(8A) is selected from unsubstituted C₃-C₁₀cycloalkyl(C₁-C₆ alkyl), unsubstituted C₆-C₁₀ aryl(C₁-C₆ alkyl),unsubstituted 5 to 10 membered heteroaryl(C₁-C₆ alkyl), andunsubstituted 3 to 10 membered heterocyclyl(C₁-C₆ alkyl).

In some embodiments, R_(8A) is selected from substituted C₃-C₁₀cycloalkyl(C₁-C₆ alkyl), substituted C₆-C₁₀ aryl(C₁-C₆ alkyl),substituted 5 to 10 membered heteroaryl(C₁-C₆ alkyl), and substituted 3to 10 membered heterocyclyl(C₁-C₆ alkyl).

In some embodiments, R₈ is R_(8B) and R_(8B) is Y₁. In some embodiments,Y₁ is

wherein Y₁ is derivatized to attach to X₂.

In some embodiments, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is NH, and R₈is a substituted phenyl or a substituted 5 or 6-membered heteroaryl,wherein the phenyl and 5 or 6-membered heteroaryl are substituted with1-3 substituents selected from hydroxyl, halogen (e.g., fluoro, chloro,and bromo), cyano, nitro, optionally substituted C₁-C₆ alkoxy (e.g.,methoxy, ethoxy, and isopropoxy), optionally substituted C₁-C₆ alkyl(e.g., methyl, ethyl, and isopropyl), optionally substituted C₃-C₈cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), andoptionally substituted 3 to 10-membered heterocyclyl (e.g.,pyrrolidinyl, morpholino, piperidinyl, piperazinyl, and azepanyl).

In some embodiments, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is NH, and R₈is a substituted phenyl or a substituted 5 or 6-membered heteroaryl,wherein the phenyl and 5 or 6-membered heteroaryl are substituted with1-3 substituents selected from hydroxyl, halogen (e.g., fluoro, chloro,and bromo), cyano, nitro, unsubstituted C₁-C₆ alkoxy (e.g., methoxy,ethoxy, and isopropoxy), unsubstituted C₁-C₆ alkyl (e.g., methyl, ethyl,and isopropyl), unsubstituted C₃-C₈ cycloalkyl (e.g., cyclopropyl,cyclobutyl, and cyclopentyl), and unsubstituted 3 to 10-memberedheterocyclyl (e.g., pyrrolidinyl, morpholino, piperidinyl, piperazinyl,and azepanyl).

In some embodiments, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is —CH₂— or—CH₂CH₂—, and R₈ is a substituted phenyl or a substituted 5 or6-membered heteroaryl, wherein the phenyl and 5 or 6-membered heteroarylare substituted with 1-3 substituents selected from hydroxyl, halogen(e.g., fluoro, chloro, and bromo), cyano, nitro, optionally substitutedC₁-C₆ alkoxy (e.g., methoxy, ethoxy, and isopropoxy), optionallysubstituted C₁-C₆ alkyl (e.g., methyl, ethyl, and isopropyl), optionallysubstituted C₃-C₈ cycloalkyl (e.g., cyclopropyl, cyclobutyl, andcyclopentyl), and optionally substituted 3 to 10-membered heterocyclyl(e.g., pyrrolidinyl, morpholino, piperidinyl, piperazinyl, andazepanyl).

In some embodiments, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is —CH₂— or—CH₂CH₂—, and R₈ is a substituted phenyl or a substituted 5 or6-membered heteroaryl, wherein the phenyl and 5 or 6-membered heteroarylare substituted with 1-3 substituents selected from hydroxyl, halogen(e.g., fluoro, chloro, and bromo), cyano, nitro, unsubstituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, and isopropoxy), unsubstituted C₁-C₆alkyl (e.g., methyl, ethyl, and isopropyl), unsubstituted C₃-C₈cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), andunsubstituted 3 to 10-membered heterocyclyl (e.g., pyrrolidinyl,morpholino, piperidinyl, piperazinyl, and azepanyl).

In some embodiments, one of R₁ and R₂ is an optionally substituted ureaand the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is NH, and R₈is a substituted phenyl or a substituted 5 or 6-membered heteroaryl,wherein the phenyl and 5 or 6-membered heteroaryl are substituted with1-3 substituents selected from hydroxyl, halogen (e.g., fluoro, chloro,and bromo), cyano, nitro, optionally substituted C₁-C₆ alkoxy (e.g.,methoxy, ethoxy, and isopropoxy), optionally substituted C₁-C₆ alkyl(e.g., methyl, ethyl, and isopropyl), optionally substituted C₃-C₈cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), andoptionally substituted 3 to 10-membered heterocyclyl (e.g.,pyrrolidinyl, morpholino, piperidinyl, piperazinyl, and azepanyl).

In some embodiments, one of R₁ and R₂ is an optionally substituted urea,and the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is NH, and R₈is a substituted phenyl or a substituted 5 or 6-membered heteroaryl,wherein the phenyl and 5 or 6-membered heteroaryl are substituted with1-3 substituents selected from hydroxyl, halogen (e.g., fluoro, chloro,and bromo), cyano, nitro, unsubstituted C₁-C₆ alkoxy (e.g., methoxy,ethoxy, and isopropoxy), unsubstituted C₁-C₆ alkyl (e.g., methyl, ethyl,and isopropyl), unsubstituted C₃-C₈ cycloalkyl (e.g., cyclopropyl,cyclobutyl, and cyclopentyl), and unsubstituted 3 to 10-memberedheterocyclyl (e.g., pyrrolidinyl, morpholino, piperidinyl, piperazinyl,and azepanyl).

In some embodiments, one of R₁ and R₂ is an optionally substituted urea,and the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is —CH₂— or—CH₂CH₂—, and R₈ is a substituted phenyl or a substituted 5 or6-membered heteroaryl, wherein the phenyl and 5 or 6-membered heteroarylare substituted with 1-3 substituents selected from hydroxyl, halogen(e.g., fluoro, chloro, and bromo), cyano, nitro, optionally substitutedC₁-C₆ alkoxy (e.g., methoxy, ethoxy, and isopropoxy), optionallysubstituted C₁-C₆ alkyl (e.g., methyl, ethyl, and isopropyl), optionallysubstituted C₃-C₈ cycloalkyl (e.g., cyclopropyl, cyclobutyl, andcyclopentyl), and optionally substituted 3 to 10-membered heterocyclyl(e.g., pyrrolidinyl, morpholino, piperidinyl, piperazinyl, andazepanyl).

In some embodiments, one of R₁ and R₂ is an optionally substituted urea,and the other of R₁ and R₂ is H, deuterium, unsubstituted C₁-C₆ alkoxy,or unsubstituted C₁-C₆ alkyl, wherein m is 1, X₃ is O, X₂ is —CH₂— or—CH₂CH₂—, and R₈ is a substituted phenyl or a substituted 5 or6-membered heteroaryl, wherein the phenyl and 5 or 6-membered heteroarylare substituted with 1-3 substituents selected from hydroxyl, halogen(e.g., fluoro, chloro, and bromo), cyano, nitro, unsubstituted C₁-C₆alkoxy (e.g., methoxy, ethoxy, and isopropoxy), unsubstituted C₁-C₆alkyl (e.g., methyl, ethyl, and isopropyl), unsubstituted C₃-C₈cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), andunsubstituted 3 to 10-membered heterocyclyl (e.g., pyrrolidinyl,morpholino, piperidinyl, piperazinyl, and azepanyl).

In some embodiments, compounds of Formula (II) are selected fromcompounds of Formula (IId), Formula (IIe), or Formula (IIf), wherein thedefinitions of R₁ and R₂ are as described herein:

In some embodiments, Y is

wherein Y is derivatized to attach to L. In some embodiments, Y is

In some embodiments, Y₁ is

wherein Y₁ is derivatized to attach to X₂. In some embodiments, Y₁ is

derivatized to attach to X₂.

As used herein, the phrases “Y is derivatized to attach to L” and “Y₁ isderivatized to attach to X₂” are used as would be understood by onehaving ordinary skill in the art. For example, when Y or Y₁ is

and Y or Y₁ is derivatized to attached to L or X₂, respectively, Y or Y₁can be:

wherein * represents the point of attachment to the L group. Similarly,when Y or Y₁ is

and Y or Y₁ is derivatized to attached to L, Y or Y₁ can be, forexample:

In some embodiments, Y and Y₁ are selected from: a compound that targetsa particular protein, proteins, and/or protein complex, such as an HSP90inhibitor, a kinase inhibitor, a phosphatase inhibitor, an estrogenreceptor agonist, an estrogen receptor antagonist, an androgen receptoragonist, an androgen receptor antagonist, an HDM2/MDM2 inhibitor, anHDAC inhibitor, a lysine methyltransferase inhibitor, or an inhibitor ofone or more core-binding factor(s). In some embodiments, and Y₁ areselected from a compound targeting: one or more ligase(s), the BETbromodomain, FKBP, acyl-protein thioesterase 1, acyl-proteinthioesterase 2, the thyroid hormone receptor, the RAF receptor, the arylhydrocarbon receptor. In some embodiments, and Y₁ are selected from animmunosuppressive compound, an angiogenesis inhibitor, an HIV proteaseinhibitor, an HIV integrase inhibitor, and an HCV protease inhibitor. Insome embodiments, Y and Y₁ are derivatized where L is attached.

In some embodiments, Y is a compound disclosed in Vallee, et al., J.Med. Chem. 54: 7206 (2011), including, but not limited to(N-[4-(3H-imidazo[4,5-C]Pyridin-2-yl)-9H-Fluoren-9-yl]-succinamide):

derivatized where a linker group L is attached, for example, via theterminal amide group.

In some embodiments, Y is(8-[(2,4-dimethylphenyl)sulfanyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):

where a linker group L is attached, for example, via the terminalacetylene group.

In some embodiments, Y is a compound disclosed in Brough, et al., “J.Med. Chem. vol: 51, page 196 (2008), including(5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylme-thyl)phenyl]isoxazole-3-carboxamide)having the structure:

derivatized, where a linker group L is attached, for example, via theamide group.

In some embodiments, Y is a compound disclosed in Wright, et al., ChemBiol., 11(6):775-85 (2004), including:

where a linker group L or is attached, for example, via the butyl group.

In some embodiments, Y is geldanamycin((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,-16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1],or a derivative thereof (e.g. 17-alkylamino-17-desmethoxygeldanamycin(“17-AAG”) or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin(“17-DMAG”)) (derivatized where a linker group L is attached, forexample, via the amide group).

In some embodiments, Y is

each derivatized either through R (representing a linker group, L), orthrough another point of attachment.

In some embodiments, Y is a compound disclosed in Millan, et al., J.Med. Chem., vol: 54, pag: 7797 (2011), including:

(1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)ureaderivatized where a linker group L is attached, for example, via theisopropyl group;

1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]-triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)ureaderivatized where a linker group L is attached, for example, via thetert-butyl group.

In some embodiments, Y is a compound disclosed in Schenkel, et al., J.Med. Chem., 54 (24), pp 8440-8450 (2011) including:

4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamideand

4-amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide,derivatized where a linker group L is attached, for example, via theterminal amide moiety.

In some embodiments, Y is a compound disclosed in Van Eis, et al.,Biorg. Med. Chem. Lett. 21(24):7367-72 (2011), including:

2-methyl-N−1-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diaminederivatized where a linker group L is attached, for example, via theterminal amino group.

In some embodiments, Y is a compound disclosed in Lountos, et al., “J.Struct. Biol., vol. 176, page 292 (2011), including:

derivatized where a linker group L is attached, for example, via eitherof the terminal hydroxyl groups.

In some embodiments, Y is

N-{4-[(1E)-N—(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamideor

N-{4-[(1E)-N-carbamidoylethanehydrazonoyl]phenyl}-1H-indole-3-carboxamidederivatized where a linker group L is attached, for example, via theterminal hydroxyl group or the hydrazone.

In some embodiments, Y is afatinib (derivatized where a linker group Lis attached, for example, via the aliphatic amine group); fostamatinib(derivatized where a linker group L is attached, for example, via amethoxy group); gefitinib (derivatized where a linker group L isattached, for example, via a methoxy or ether group); lenvatinib(derivatized where a linker group L is attached, for example, via thecyclopropyl group); vandetanib (derivatized where a linker group L isattached, for example, via the methoxy or hydroxyl group); vemurafenib(derivatized where a linker group L is attached, for example, via thesulfonyl propyl group); Gleevec (derivatized where R as a linker group Lis attached, for example, via the amide group or via the aniline aminegroup); pazopanib (derivatized where R is a linker group L attached, forexample, to the phenyl moiety or via the aniline amine group); AT-9283

(derivatized where R is a linker group L attached, for example, to thephenyl moiety); TAE684

(derivatized where R is a linker group L attached, for example, to thephenyl moiety);

(derivatized where R is a linker group L attached, for example, to thephenyl moiety or the aniline amine group);

(derivatized where R is a linker group L attached, for example, to thephenyl moiety or the diazole group);

(derivatized where R is a linker group L attached, for example, to thephenyl moiety or the diazole group);

(derivatized where R is a linker group L attached, for example, to thephenyl moiety);

(derivatized where R is a linker group L attached, for example, to thephenyl moiety or a hydroxyl or ether group on the quinoline moiety);

(derivatized where a linker group L is attached, for example, at R);

(derivatized where a linker group L is attached, for example, at R);

(derivatized where a linker group L is attached, for example, at R);

(derivatized where a linker group L is attached, for example, at R);

(derivatized where a linker group L is attached, for example, at R);

(derivatized where a linker group L is attached, for example, at R); or

(derivatized where a linker group L is attached, for example, at R).

In some embodiments, Y is a compound disclosed in Vassilev, et al.,Science, vol. 303, pages 844-848 (2004), and Schneekloth, et al.,Bioorg. Med. Chem. Lett., vol. 18, pages 5904-5908 (2008), includingnutlin-3, nutlin-2, and nutlin-1 (shown below):

(derivatized where a linker group L is attached, for example, at themethoxy group or as a hydroxyl group);

(derivatized where a linker group L is attached, for example, at themethoxy group or hydroxyl group);

(derivatized where a linker group L is attached, for example, via themethoxy group or as a hydroxyl group); andtrans-4-Iodo-4′-Boranyl-Chalcone

(derivatized where a linker group L or a linker group L is attached, forexample, via a hydroxy group).

In some embodiments, Y is one of the compounds shown below, derivatizedby the attachment of a linker group L (in some instances denoted by “R,”below).

In some embodiments, Y is azacitidine ((derivatized where a linker groupL is attached, for example, via the hydroxy or amino groups). In someembodiments, Y is decitabine (derivatized)(4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one)(derivatized where a linker group L is attached, for example, via eitherof the hydroxy groups or at the amino group).

In some embodiments, Y is GA-1 (derivatized) and derivatives and analogsthereof, having the structure(s) and binding to linkers as described inSakamoto, et al., Development of Protacs to target cancer-promotingproteins for ubiquitination and degradation, Mol Cell Proteomics,2(12):1350-58 (2003).

In some embodiments, Y is estradiol or testosterone, and relatedderivatives (including, but not limited to, DHT) which may be bound to alinker group L as is generally described in Rodriguez-Gonzalez, et al.,Oncogene, 27, 7201-7211 (2008) and/or Sakamoto, et al., Mol CellProteomics, 2(12):1350-58 (2003).

In some embodiments, Y is ovalicin, fumagillin, a glucocorticoid(including, but not limited to hydrocortisone, prednisone, prednisolone,and methylprednisolone), methotrexate, cyclosporine, tacrolimus(FK-506), rapamycin, apigenin, or an actinomycin, each derivatized wherea linker group L is bound.

In some embodiments, Y is

where “R” designates a site for linker group L or group attachment, forexample.

In some embodiments, Y is a compound disclosed in Cancer Research(2006), 66(11), 5790-5797, including but not limited to the Bcr-Abltyrosine-kinase inhibitor dasatinib, derivatized where R is a linkergroup L attached, for example, via an ether or other functional group.

In some embodiments, Y is a compound disclosed in Cancer Cell (2007),11(3), 209-11, including but not limited to the epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitor shown below, derivatized whereR is a linker group L attached, for example, via an ether or otherfunctional group.

This compound below is replacing [0419] In some embodiments, Y is acompound disclosed in PLoS One (2014), 9(10), e109705/1-e109705/12,including but not limited to the AKT kinase inhibitor shown below,derivatized where R is a linker group L attached, for example, via anamide or other functional group.

In some embodiments, Y is a compound disclosed in Scientific Reports(2015), 5, 14538, including but not limited to the Janus kinase 2 (JAK2)kinase inhibitor shown below, derivatized where R is a linker group Lattached, for example, via an ether or other functional group.

In some embodiments, Y is a CK1α kinase inhibitor including but notlimited to the compound shown below, derivatized where R is a linkergroup L attached, for example, via an amide or other functional group.

In some embodiments, Y is a compound disclosed in Journal of MedicinalChemistry (2013), 56(14), 5979-5983, including but not limited to theMDM2 inhibitor shown below, derivatized where R is a linker group Lattached, for example, via an amide or other functional group.

In some embodiments, Y is a compound disclosed in Proceedings of theNational Academy of Sciences of the United States of America (2015),112(51), 15713-15718, including but not limited to thebromodomain-containing protein 4 (BRD4) inhibitor shown below,derivatized where R is a linker group L attached, for example, via anamide or other functional group.

In some embodiments, Y is a compound disclosed in Journal of MedicinalChemistry (2010), 53(7), 2779-2796, including but not limited to theandrogen receptor (AR) modulator shown below, derivatized where R is alinker group L attached, for example, via an ether or other functionalgroup.

In some embodiments, Y is a compound disclosed in Journal of MedicinalChemistry (2011), 54(3), 788-808, including but not limited to theestrogen receptor alpha (ERα) modulator shown below, derivatized where Ris a linker group L attached, for example, to the nitrogen of thethiazolidinedione.

In some embodiments, Y is a compound disclosed in Chemistry & Biology(Cambridge, Mass., United States) (2007), 14(10), 1186-1197, includingbut not limited to the core-binding factor beta (CBFβ) inhibitor shownbelow, derivatized where R is a linker group L attached, for example,via an amide or other functional group.

Some embodiments provide a compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein: Q₁,Q₂, and Q₃, are each independently CR₁, CR₂, or —S—, and at least one ofQ₁, Q₂, and Q₃, is CR₁ or CR₂; each

is independently selected from a carbon-carbon double bond, acarbon-carbon single bond, and a carbon-sulfur single bond; R₁ and R₂are each independently H, deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted amino, optionally substituted C-amido, optionallysubstituted N-amido, optionally substituted ester, optionallysubstituted urea, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 3to 10-membered heterocyclyl, optionally substituted 5 to 10-memberedheteroaryl,

or L-Y; wherein when one of R₁ or R₂ is H or

the other of R₁ or R₂ is not L-Y; R₅ is H, deuterium, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₂-C₆ alkenyl; X isC(R₅)₂, CH(R₅), CH₂, C═O, or C═S; X₁ is selected from H, deuterium,halogen, and optionally substituted C₁-C₆ alkyl; X₂ is selected from(CH₂)_(a), (CD₂)_(a), (CF₂)_(a), C═O, NH, N—(optionally substitutedC₁-C₆ alkyl), and [(CH₂)_(p)—O—(CH₂)_(q)]_(r); X₃ is selected from O,NH, and S; a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 1, 2, or 3; mis 1, 2, 3, 4, or 5; p and q are independently 0, 1, 2, 3, 4, 5, or 6; ris 0, 1, 2, 3, or 4; Qa and Qb are each independently C═O or C═S;wherein when n is 2, then Q₃ is —S—, or when n is 2, then R₁ issubstituted C₁-C₆ alkyl,

optionally substituted C₃-C₈ cycloalkyl, optionally substituted 3 to10-membered heterocyclyl, optionally substituted 5 to 10-memberedheteroaryl, optionally substituted urea, or L-Y; L is—Z₁—(R₆—O—R₆)_(t)—Z₂—; —Z₁(R₆—NH—R₆)_(t)—Z₂—; —Z₁—(R₆—S—R₆)_(t)—Z₂—;—Z₁—(R₆—(C═O)—R₆)_(t)—Z₂—; —Z₁—(R₆—(CO₂)—R₆)_(t)—Z₂—;—Z₁—(R₆—(NHCO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(CONH)—R₆)_(t)—Z_(2-Z)—(R₆—(SO)—R₆)_(t)—Z₂—;—Z₁—(R₆—(SO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═NH)NH—R₆)_(t)—Z₂—;—Z₁—(R₆—(NHSO₂)—R₆)_(t)—Z₂—; —Z₁—(R₆—(SO₂NH)—R₆)_(t)—Z₂—;—Z₁—(R₆—NH(C═O)NH—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(C═S)NH—R₆)_(t)—Z₂—; or—Z₁—(R₆-R₇—R₆)_(t)—Z₂—; each t is independently 1, 2, 3, 4, 5, 6, 7, or8; Z₁ and Z₂ are each independently —CH₂—; —O—; —S—; S═O; —SO₂—; C═O;—CO₂—; —NH—; —NH(CO)—; —(CO)NH—; —NH—SO₂—; —SO₂—NH—; —R₆CH₂—; —R₆O—;—R₆S—; —R₆—S═O; —R₆SO₂—; —R₆—C═O; —R₆CO₂—; —R₆NH—; —R₆NH(CO)—;—R₆(CO)NH—; —R₆NH—SO₂—; —R₆SO₂—NH—; —CH₂R₆—; —OR₆—; —SR₆—; —S═O—R₆;—SO₂R₆—; —C═O—R₆; —CO₂R₆—; —NHR₆—; —NH(CO)R₆—; —(CO)NHR₆—; —NH—SO₂R₆—;or —SO₂—NHR₆—; each R₆ is absent, or independently C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl, 3 to 10-membered heterocyclyl, or 5to 10-membered heteroaryl; R₇ is optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 3to 10-membered heterocyclyl, or optionally substituted 5 to 10-memberedheteroaryl; R₈ is selected from optionally substituted C₃-C₁₀cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 5to 10-membered heteroaryl, optionally substituted 3 to 10-memberedheterocyclyl, optionally substituted C₁-C₁₀ alkyl, R_(8A) and R_(8B);R_(8A) is selected from hydroxyl, halogen, cyano, nitro, unsubstitutedamino, mono-substituted amino, di-substituted amino, optionallysubstituted C-amido, optionally substituted N-amido, optionallysubstituted ester, optionally substituted sulfonyl, optionallysubstituted S-sulfonamido, optionally substituted N-sulfonamido,optionally substituted sulfonate, optionally substituted O-thiocarbamyl,optionally substituted N-thiocarbamyl, optionally substitutedN-carbamyl, optionally substituted O-carbamyl, optionally substitutedurea, optionally substituted thiourea, optionally substituted C₁-C₆alkoxy, optionally substituted C₁-C₆ haloalkoxy, optionally substitutedC₃-C₁₀ cycloalkyl(C₁-C₆ alkyl), optionally substituted C₆-C₁₀ aryl(C₁-C₆alkyl), optionally substituted 5 to 10 membered heteroaryl(C₁-C₆ alkyl),and optionally substituted 3 to 10 membered heterocyclyl(C₁-C₆ alkyl);R_(8B) is Y₁; Y and Y₁ are independently selected from

wherein Y is derivatized to attach to L and Y₁ is derivatized to attachto X₂. In some embodiments, the compound of Formula (II) is selectedfrom compounds of Formula (IIa)

Formula (IIb)

and Formula (IIc)

or a pharmaceutically acceptable salt of any of the foregoing. In someembodiments, wherein the compound of Formula (II) is selected fromFormulae (IId), (IIe) and (IIf):

pharmaceutically acceptable salt thereof. In some embodiments, Qa is C═Oand Qb is C═O. In some embodiments, n is 2. In some embodiments, n is 3.In some embodiments, R₅ is H. In some embodiments, X is CH₂. In someembodiments, X₁ is selected from H, deuterium, and fluoro. In someembodiments, R₁ is optionally substituted C₃-C₆ cycloalkyl or optionallysubstituted C₁-C₆ alkyl; or R₂ is optionally substituted C₃-C₆cycloalkyl or optionally substituted C₁-C₆ alkyl. In some embodiments,wherein:L is —Z₁—(R₆—O—R₆)_(t)—Z₂—; —Z₁(R₆—NH—R₆)_(t)—Z₂—;—Z₁—(R₆—(NHCO)—R₆)_(t)—Z₂—; —Z₁—(R₆—NH(CO)NH—R₆)_(t)—Z₂—;—Z—(R₆—NH(C═NH)NH—R₆)_(t)—Z₂—; —Z—(R₆—NH(C═S)NH—R₆)_(t)—Z₂—; or—Z₁—(R₆—(CONH)—R₆)_(t)—Z₂—; t is 1, 2, 3, or 4; and Z₁ and Z₂ are eachindependently —CH₂—; —O—; —NH—; —NH(CO)—; or —(CO)NH—. In someembodiments, one of R₁ and R₂ is an optionally substituted urea, and theother of R₁ and R₂ is H, fluoro, optionally substituted C₁-C₆ alkyl oroptionally substituted C₃-C₆ cycloalkyl. In some embodiments, one of R¹and R² is selected from

In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. Insome embodiments, X₃ is O or S. In some embodiments, X₂ is (CH₂)_(a). Insome embodiments, a is 2 or 3. In some embodiments, X₂ is NH. In someembodiments, m is 1, 2, or 3; X₂ is NH; and X₃ is O or S. In someembodiments, R₈ is selected from an optionally substituted C₃-C₁₀cycloalkyl, an optionally substituted C₆-C₁₀ aryl, an optionallysubstituted 5 to 10-membered heteroaryl, and an optionally substituted 3to 10-membered heterocyclyl. In some embodiments, the optionallysubstituted C₆-C₁₀ aryl is a mono-substituted phenyl group, adi-substituted phenyl group, or a tri-substituted phenyl group. In someembodiments, the optionally substituted C₆-C₁₀ aryl is a phenyl groupsubstituted with halogen, a phenyl group substituted with anunsubstituted C₁-C₆ alkyl, a phenyl group substituted with anunsubstituted C₁-C₆ alkyl and halogen, a phenyl group substituted withan unsubstituted C₁-C₆ alkyl and an unsubstituted C₁-C₃ alkoxy, a phenylgroup substituted with an unsubstituted C₁-C₃ alkoxy and halogen, aphenyl group substituted with an unsubstituted C₁-C₆ alkyl and anunsubstituted di(C₁-C₃ alkyl)amino, or a phenyl group substituted withan unsubstituted di(C₁-C₃ alkyl)amino and halogen. In some embodiments,R₈ is selected from a 5-6 membered heteroaryl group substituted withhalogen, a 5-6 membered heteroaryl group substituted with anunsubstituted C₁-C₆ alkyl, a 5-6 membered heteroaryl group substitutedwith an unsubstituted C₁-C₆ alkyl and halogen, a 5-6 membered heteroarylgroup substituted with an unsubstituted C₁-C₆ alkyl and an unsubstitutedC₁-C₃ alkoxy, a 5-6 membered heteroaryl group substituted with anunsubstituted C₁-C₃ alkoxy and halogen, a 5-6 membered heteroaryl groupsubstituted with an unsubstituted C₁-C₆ alkyl and an unsubstituteddi(C₁-C₃ alkyl)amino, or a 5-6 membered heteroaryl group substitutedwith an unsubstituted di(C₁-C₃ alkyl)amino and halogen. In someembodiments, R₈ is R_(8A) and R_(8A) is selected from: optionallysubstituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl), optionally substitutedC₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted 5 to 10 memberedheteroaryl(C₁-C₆ alkyl), and optionally substituted 3 to 10 memberedheterocyclyl(C₁-C₆ alkyl). In some embodiments, R₈ is R_(8B); R_(8B) isY₁; and Y₁ is

wherein Y₁ is derivatized to attach to X₂. Some embodiments provide apharmaceutical composition comprising a compound of Formula (II), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. Some embodiments provide a methodof treating, ameliorating, or preventing a disease, disorder, orcondition associated with a protein selected from a cytokine, aiolos,ikaros, helios, CK1α, GSPT1, and combinations of any of the foregoing,the method comprising administering a therapeutically effective amountof a compound of Formula (II), or a pharmaceutically acceptable saltthereof; wherein the disease, disorder, or condition is selected frominflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease,Alzheimer's disease, and cancer. Some embodiments provide a method ofinhibiting protein activity, comprising contacting a cell with acompound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein the protein is aiolos, ikaros, helios, CK1α, GSPT1, a cytokine,or a combination of any of the foregoing.

In some embodiments, the compound of Formula (II) is selected from

or pharmaceutically acceptable salts or solvates thereof.

In some embodiments, Q₁ is —S—, Q₂ is CR₁, Q₃ is CR₂, Qa and Qb are eachC═O, n is 2, X is CH₂, and each of X₁, R₁, R₂, R₅, and R₇ areindependently selected from hydrogen, deuterium, substituted alkyl, andunsubstituted alkyl. In some embodiments, Q₁ is CR₁, Q₂ is —S—, Q₃ isCR₂, n is 2, X is CH₂, and each of X₁, R₁, R₂, R₅, and R₇ areindependently selected from hydrogen, deuterium, substituted alkyl, andunsubstituted alkyl.

In some embodiments, Q₁ is —S—, Q₂ is CR₁, Q₃ is CR₂, Qa and Qb are eachC═O, n is 2, X is CH₂, each of X₁, R₅, and R₇ are independently selectedfrom hydrogen, deuterium, substituted alkyl, and unsubstituted alkyl,one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl. In some embodiments,Q₁ is CR₁, Q₂ is —S—, Q₃ is CR₂, n is 2, X is CH₂, each of X₁, R₅, andR₇ are independently selected from hydrogen, deuterium, substitutedalkyl, and unsubstituted alkyl, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is —S—, Q₂ is CR₁, Q₃ is CR₂, Qa and Qb are eachC═O, n is 2, X is C═O, and each of X₁, R₁, R₂, R₅, and R₇ areindependently selected from hydrogen, deuterium, substituted alkyl, andunsubstituted alkyl. In some embodiments, Q₁ is CR₁, Q₂ is —S—, Q₃ isCR₂, n is 2, X is C═O, and each of X₁, R₁, R₂, R₅, and R₇ areindependently selected from hydrogen, deuterium, substituted alkyl, andunsubstituted alkyl.

In some embodiments, Q₁ is —S—, Q₂ is CR₁, Q₃ is CR₂, Qa and Qb are eachC═O, n is 2, X is C═O, each of X₁ and R₅ are independently selected fromhydrogen, deuterium, substituted alkyl, and unsubstituted alkyl, one ofR₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl. In some embodiments,Q₁ is CR₁, Q₂ is —S—, Q₃ is CR₂, n is 2, X is C═O, each of X₁ and R₅ areindependently selected from hydrogen, deuterium, substituted alkyl, andunsubstituted alkyl, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa and Qb are each C═O, n is1, and X is CH₂.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa and Qb are each C═O, n is 1, X is CH₂, oneof R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa is C═O and Qb is C═O orCH₂, n is 1, and X is CH₂.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa is C═O and Qb is C═O or CH₂, n is 1, X isCH₂, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa is C═O and Qb is C═O orCH₂, n is 1, and X is C═O.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa is C═O and Qb is C═O or CH₂, n is 1, X isC═O, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa is C═O and Qb is C═O orCH₂, n is 1, and X is C═O.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa is C═O and Qb is C═O or CH₂, n is 1, X isC═O, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa and Qb are each C═O, n is2, and X is CH₂.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa and Qb are each C═O, n is 2, X is CH₂, oneof R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa is C═O and Qb is C═O orCH₂, n is 2, and X is CH₂.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa is C═O and Qb is C═O or CH₂, n is 2, X isCH₂, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa and Qb are each C═O, n is2, and X is C═O.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa and Qb are each C═O, n is 2, X is C═O, oneof R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁, R₁,R₂, R₅, and R₇ are independently selected from hydrogen, deuterium,substituted alkyl, and unsubstituted alkyl, Qa is C═O and Qb is C═O orCH₂, n is 2, and X is C═O.

In some embodiments, Q₁ is CR₂, Q₂ is CR₁, Q₃ is —S—, each of X₁ and R₅are independently selected from hydrogen, deuterium, substituted alkyl,and unsubstituted alkyl, Qa is C═O and Qb is C═O or CH₂, n is 2, X isC═O, one of R₁ and R₂ is

and the other of R₁ and R₂ is H, substituted alkyl, or unsubstitutedalkyl, X₃ is O, m is 1, X₂ is NH or CH₂, and R₈ is a substituted C₆-C₁₀aryl or a substituted 5 to 10-membered heteroaryl.

Some embodiments provide a pharmaceutical composition comprising acompound of Formula (II) and at least one pharmaceutically acceptablecarrier. Some embodiments provide a pharmaceutical compositioncomprising a pharmaceutically acceptable salt or a solvate of a compoundof Formula (II) and at least one pharmaceutically acceptable carrier.The definitions for compounds of Formula (II) are the same as those setforth above.

Some embodiments provide a pharmaceutical composition comprising acompound of Formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), and atleast one pharmaceutically acceptable carrier. Some embodiments providea pharmaceutical composition comprising a pharmaceutically acceptablesalt or a solvate of a compound of Formula (IIa), (IIb), (IIc), (IId),(IIe) or (IIf), and at least one pharmaceutically acceptable carrier.The definitions for compounds of Formula (II) are the same as those setforth above.

Some embodiments provide methods of treating, ameliorating, orpreventing a disease, disorder, or condition associated with cytokines,comprising administering a therapeutically effective amount of acompound of Formula (II). Some embodiments provide methods of treating,ameliorating, or preventing a disease, disorder, or condition associatedwith cytokines, comprising administering a therapeutically effectiveamount of a compound of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe)or (IIf). Some embodiments provide methods of treating, ameliorating, orpreventing a disease, disorder, or condition associated with cytokines,comprising administering a pharmaceutically acceptable salt of solvateof a compound of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or(IIf). The definitions for compounds of Formula (II) are the same asthose set forth above.

In some embodiments, the disease, disorder, or condition selected frominflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease,Alzheimer's disease, and cancer.

Some embodiments provide methods of inhibiting cytokine activity,comprising contacting a cell with a compound of Formula (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf). Some embodiments provide methods ofinhibiting cytokine activity, comprising contacting a cell with apharmaceutically acceptable salt or a solvate of a compound of Formula(II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf). The definitions forcompounds of Formula (II) are the same as those set forth above.

Some embodiments provide methods of treating, ameliorating, orpreventing a disease, disorder, or condition associated with GSPT1function or imbalance, comprising administering a therapeuticallyeffective amount of a compound of Formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf). Some embodiments provide methods of treating,ameliorating, or preventing a disease, disorder, or condition associatedwith protein function or imbalance, comprising administering apharmaceutically acceptable salt of solvate of a compound of Formula(II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), to a subject in needthereof. The definitions for compounds of Formula (II), (IIa), (IIb),(IIc), (IId), (IIe) or (IIf) are the same as those set forth above.

In some embodiments of the method for treating, ameliorating, orpreventing a disease, disorder, or condition associated with GSPT1function or imbalance, the disease, disorder, or condition is selectedfrom cancer (for example, breast cancer, hepatocellular carcinoma,gastric cancer, and prostate cancer) and astrogliosis. In someembodiments, the cancer is breast cancer. In some embodiments, thecancer is hepatocellular carcinoma. In some embodiments, the cancer isgastric cancer. In some embodiments, the cancer is prostate cancer. Insome embodiments, the disease, disorder, or condition is astrogliosis.

Some embodiments provide methods of inhibiting GSPT1 activity,comprising contacting a cell with a compound of Formula (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf). Some embodiments provide methods ofinhibiting GSPT1 activity, comprising contacting a cell with apharmaceutically acceptable salt of a compound of Formula (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf). The definitions for compounds ofFormula (I) are the same as those set forth above.

Some embodiments provide methods of treating, ameliorating, orpreventing a disease, disorder, or condition associated with GSPT1malfunction, comprising administering a therapeutically effective amountof a compound of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or(IIf), or a pharmaceutically acceptable salt thereof, to a subject inneed thereof.

In some embodiments, the disease, disorder, or condition is cancer. Insome embodiments the cancer is selected from breast cancer,hepatocellular carcinoma, gastric cancer, and prostate cancer. In someembodiments, the disease, disorder, or condition is astrogliosis.

Some embodiments provide methods of treating, ameliorating, orpreventing a disease, disorder, or condition associated with a proteinselected from a cytokine, aiolos, ikaros, helios, CK1α, and combinationsof any of the foregoing, the method comprising administering atherapeutically effective amount of a compound Formula (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf), or a pharmaceutically acceptablesalt thereof.

In some embodiments, the disease, disorder, or condition is selectedfrom inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease,Alzheimer's disease, and cancer.

Some embodiments provide methods of inhibiting protein activity,comprising contacting a cell with a compound of Formula (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf), or a pharmaceutically acceptablesalt thereof, wherein the protein is aiolos, ikaros, helios, CK1α, acytokine, or a combination of any of the foregoing.

Some embodiments provide methods of decreasing the risk of skin cancerin a subject in need thereof, comprising administering an effectiveamount of a compound of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe)or (IIf), or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods for treating, ameliorating, orpreventing a skin disorder, disease, or condition in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe)or (IIf), or a pharmaceutically acceptable salt thereof. In someembodiments, the skin disorder, disease, or condition is sunburn or skinhypopigmentation.

Some embodiments provide methods for treating, ameliorating, orpreventing a skin disorder, disease, or condition in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (II), (IIa), (IIb), (IIc), (IId), (IIe)or (IIf), or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods for increasing skin pigmentation in asubject in need thereof, comprising administering a therapeuticallyeffective amount of a compound of Formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf), or a pharmaceutically acceptable salt thereof. Insome embodiments, the administering comprises contacting the skin with atherapeutically effective amount of Formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf), or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods for increasing eumelanin level in asubject in need thereof, comprising administering a therapeuticallyeffective amount of a compound of Formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf), or a pharmaceutically acceptable salt thereof. Insome embodiments, administering comprises contacting the skin with atherapeutically effective amount of a compound of Formula (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf), or a pharmaceutically acceptablesalt thereof.

Some embodiments provide methods for increasing p53 activity, comprisingcontacting a cell with a compound of Formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf), or a pharmaceutically acceptable salt thereof.Some embodiments provide methods for decreasing MDM2 activity,comprising contacting a cell with a compound of Formula (II), (IIa),(IIb), (IIc), (IId), (IIe) or (IIf), or a pharmaceutically acceptablesalt thereof.

In some embodiments the subject in need thereof is known to possess oneor more of wild-type GSPT1, p53, MDM2, CK1α, aiolos, helios, or ikaros.In some embodiments the subject in need thereof is known to possess oneor more of aberrant GSPT1, p53, MDM2, CK1α, aiolos, helios, or ikaros.

In some embodiments, the compound of Formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf) is administered in combination with a secondtherapeutic agent. In some embodiments the second therapeutic agent isselected from anti-inflammatory agents, anti-cancer agents,immunostimulatory agents, and immunosuppressive agents. In someembodiments the second therapeutic agent is anti-cancer agent.

One or more of the compounds of preferred embodiments can be provided inthe form of pharmaceutically acceptable salts, solvates, activemetabolites, tautomers, or prodrugs thereof. Some embodiments can beprovided in pharmaceutical compositions comprising a therapeuticallyeffective amount of the compound. In some embodiments, thepharmaceutical composition also contains at least one pharmaceuticallyacceptable inactive ingredient. The pharmaceutical composition can beformulated for intravenous injection, subcutaneous injection, oraladministration, buccal administration, inhalation, nasal administration,topical administration, transdermal administration, ophthalmicadministration, or otic administration. The pharmaceutical compositioncan be in the form of a tablet, a pill, a capsule, a liquid, aninhalant, a nasal spray solution, a suppository, a suspension, a gel, acolloid, a dispersion, a solution, an emulsion, an ointment, a lotion,an eye drop, or an ear drop.

In some embodiments, the pharmaceutical composition is formulated as agel, salve, ointment, cream, emulsion, or paste for topical applicationto the skin.

The pharmaceutical compositions of preferred embodiments can furthercomprise one or more additional therapeutically active agents other thana compound of the preferred embodiments. Such agents can include, butare not limited to, anti-inflammatory agents, anti-cancer agents,immunostimulatory agents, and immunosuppressive agents.

Other objects, features, and advantages of the compounds, methods, andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. The use of “or” or “and” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. As used in this specification, whether in a transitionalphrase or in the body of the claim, the terms “comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. Thatis, the terms are to be interpreted synonymously with the phrases“having at least” or “including at least.” When used in the context of aprocess, the term “comprising” means that the process includes at leastthe recited steps, but may include additional steps. When used in thecontext of a compound, composition, or device, the term “comprising”means that the compound, composition, or device includes at least therecited features or components, but may also include additional featuresor components.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

As used herein, common organic abbreviations are defined as follows:

° C. Temperature in degrees Centigrade

DCM Dichloromethane (Methylene chloride)

DMSO Dimethylsulfoxide

EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

EA Ethyl acetate

g Gram(s)

h or hr H(s)

HCl Hydrochloric acid

HOBt Hydroxybenzotriazole

IL Interleukin

LPS Lipopolysaccharide

M-CSF Macrophage colony-stimulating factor

MeOH Methanol

MS Mass spectrometry

mg Milligram(s)

mL Milliliter(s)

NaCl Sodium chloride

NaOH Sodium hydroxide

NBS N-Bromosuccinimide

PBMC Peripheral blood mononuclear cell

PG Protecting group

ppt Precipitate

psi Pounds per square inch

RPMI Roswell Park Memorial Institute medium

rt Room temperature

TNF Tumor necrosis factor

μL Microliter(s)

μM Micromolar

wt. weight

The terms “co-administration” and similar terms as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation toadministration of the selected therapeutic agents to a single patient,and are intended to include treatment regimens in which the agents areadministered by the same or different route of administration or at thesame or different time.

The terms “effective amount” and “therapeutically effective amount” arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount of an agent or a compound being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case may be determined using techniques, suchas a dose escalation study. Where a drug has been approved by the U.S.Food and Drug Administration (FDA) or a counterpart foreign medicinesagency, a “therapeutically effective amount” optionally refers to thedosage approved by the FDA or its counterpart foreign agency fortreatment of the identified disease or condition.

The term “pharmaceutical combination” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a product thatresults from the mixing or combining of more than one active ingredientand includes both fixed and non-fixed combinations of the activeingredients. The term “fixed combination” means that the activeingredients, e.g., a compound of a preferred embodiment and a co-agent,are both administered to a patient simultaneously in the form of asingle entity or dosage. The term “non-fixed combination” means that theactive ingredients, e.g., a compound of a preferred embodiment and aco-agent, are administered to a patient as separate entities eithersimultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g., the administration of three or moreactive ingredients.

As used herein, any “R” group(s) such as, without limitation, R₂, R₃,R₄, R₅, R₆, R₉, and R₁₀ represent substituents that can be attached tothe indicated atom. An R group may be substituted or unsubstituted. Iftwo “R” groups are described as being “taken together” the R groups andthe atoms they are attached to can form a cycloalkyl, aryl, heteroaryl,or heterocycle. For example, without limitation, if R² and R³, or R²,R³, or R⁴, and the atom to which it is attached, are indicated to be“taken together” or “joined together” it means that they are covalentlybonded to one another to form a ring:

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “optionally substituted”or “substituted” group may be individually and independently substitutedwith one or more group(s) individually and independently selected fromalkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl(branched and straight-chained)), alkenyl (for example, vinyl, allyl,isopropenyl, n-butenyl, isobutenyl, pentenyl (branched andstraight-chained), and hexenyl (branched and straight-chained)), alkynyl(for example, ethynyl, propynyl, butynyl, pentynyl (branched andstraight-chained), and hexynyl (branched and straight-chained)),cycloalkyl (for example, C₃-C₁₀ cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, aswell as bicyclic C₃-C₁₀ cycloalkyl groups such as bridged, fused, andspiro C₃-C₁₀ cycloalkyl groups), cycloalkenyl, (for example, ringsincluding a single carbon-carbon double bond, such as cyclopropenyl,cyclobutenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl, and ringswith two or more carbon-carbon double bonds, such as cyclohexa-1,3-dieneand cyclohepta-1,3-diene), cycloalkynyl (for example, cycloheptynyl, andcyclooctynyl), aryl (for example, phenyl and naphthyl), heteroaryl (forexample, monocyclic and bicyclic 3-10 membered heteroaryl groups withone nitrogen atom, two nitrogen atoms, three nitrogen atoms, fournitrogen atoms, one oxygen atom, one sulfur atom, one oxygen atom andone or two nitrogen atoms, and one sulfur atom and one or two nitrogenatoms), heterocyclyl (for example, monocyclic and bicyclic (includingfused, bridged, and spiro) 3-10 membered heterocyclyl groups with onenitrogen atom, two nitrogen atoms, three nitrogen atoms, four nitrogenatoms, one oxygen atom, one sulfur atom, one oxygen atom and one or twonitrogen atoms, and one sulfur atom and one or two nitrogen atoms),aralkyl (for example, phenyl(C₁-C₆ alkyl) and naphthyl(C₁-C₆ alkyl)),heteroaralkyl (for example, monocyclic and bicyclic 3-10 memberedheteroaryl(C₁-C₆ alkyl) groups with one nitrogen atom, two nitrogenatoms, three nitrogen atoms, four nitrogen atoms, one oxygen atom, onesulfur atom, one oxygen atom and one or two nitrogen atoms, and onesulfur atom and one or two nitrogen atoms), (heterocyclyl)alkyl, (forexample, monocyclic and bicyclic (including fused, bridged, and spiro)3-10 membered heterocyclyl(C₁-C₆ alkyl) groups with one nitrogen atom,two nitrogen atoms, three nitrogen atoms, four nitrogen atoms, oneoxygen atom, one sulfur atom, one oxygen atom and one or two nitrogenatoms, and one sulfur atom and one or two nitrogen atoms),(cycloalkyl)alkyl (for example, C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl) groupssuch as cyclopropyl(C₁-C₆ alkyl), cyclobutyl(C₁-C₆ alkyl),cyclohexyl(C₁-C₆ alkyl), cycloheptyl(C₁-C₆ alkyl), and cyclooctyl(C₁-C₆alkyl), as well as bicyclic C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl) groups suchas bridged, fused, and spiro C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl) groups),hydroxy, protected hydroxyl (for example, methoxymethyl ether,tetrahydropyranyl ether, t-butyl ether, allyl ether, benzyl ether, silylether, acetic acid ester, benzoic acid ester, or pivalic acid ester),alkoxy (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, pentoxy (branched and straight-chained), andhexoxy (branched and straight-chained)), aryloxy (for example, phenoxyor naphtyloxy), acyl (for example, formyl or acetyl), cyano, halogen(for example fluoro, chloro, bromo, or iodo), thiocarbonyl,heterocyclyl(alkoxy) (for example, a 3-10 membered heterocyclyl(C₁-C₆alkoxy), including monocyclic and bicyclic (fused, bridged, and spiro)3-10 membered heterocyclyl(C₁-C₆ alkoxy) groups with the heterocyclylgroup having one nitrogen atom, two nitrogen atoms, three nitrogenatoms, four nitrogen atoms, one oxygen atom, one sulfur atom, one oxygenatom and one or two nitrogen atoms, and one sulfur atom or one or twonitrogen atoms, such as morpholino(ethoxy), morpholino(n-propoxy),morpholino(n-butoxy), piperidinyl(ethoxy), piperidinyl(n-propoxy),piperidinyl(n-butoxy), piperazinyl(ethoxy), piperazinyl(n-propoxy), andpiperazinyl(n-butoxy)), C-amido (for example, carboxamide,N,N-dimethylcarboxamide, N,N-dimethylcarboxamide, andN-methyl-N-phenylcarboxamide), N-amido (for example, formamide,acetamide, and phenylacetamide), C-carboxy (for example, a C₁-C₆ alkylester, an aralkyl ester, and a C₆-C₁₀ aryl ester), protected C-carboxy(for example, a S-t-butyl ester or a 1,3-oxazoline), O-carboxy (forexample, a C₁-C₆ alkyl carboxylate, an aralkyl carboxylate, and a C₆-C₁₀aryl carboxylate), nitro, silyl (for example, tri-methylsilyl,tri-ethylsilyl, tri-isopropyl silyl, and t-butyldimethylsilyl),haloalkyl (for example, a C₁-C₆ haloalkyl, a C₁-C₆ fluoroalkyl, a C₁-C₆chloroalkyl, a C₁-C₆ chlorofluoroalkyl, including C₁-C₆ haloalkyl groupswith one fluorine atom, two fluorine atoms, three fluorine, atoms, fourfluorine atoms, five fluorine atoms, one chlorine atom, two chlorineatoms, three chlorine atoms, or any combination thereof, such as —CH₂F,—CHF₂, —CF₃, —CCl₃, —CH₂CHF₂, —CH₂CF₃, and —CF₂CF₃), haloalkoxy (forexample, a C₁-C₆ haloalkoxy, a C₁-C₆ fluoroalkoxy, a C₁-C₆ chloroalkoxy,a C₁-C₆ chlorofluoroalkoxy, including C₁-C₆ haloalkoxy groups with onefluorine atom, two fluorine atoms, three fluorine, atoms, four fluorineatoms, five fluorine atoms, one chlorine atom, two chlorine atoms, threechlorine atoms, or any combination thereof, such as —OCH₂F, —OCHF₂,—OCF₃, —OCH₂CHF₂, —OCH₂CF₃, and —OCF₂CF₃), trihalomethanesulfonyl (forexample, trifluoromethanesulfonyl), trihalomethanesulfonamido (forexample, trifluoromethanesulfonamido), amino, dialkylamino(alkyl) (forexample, dimethylamino(C₁-C₆ alkyl), diethylamino(C₁-C₆ alkyl),diisopropylamino(C₁-C₆ alkyl), methylethylmino(C₁-C₆ alkyl),dimethylamino(ethyl), diethylamino(ethyl), diisopropylamino(ethyl), andmethylethylmino(ethyl)), mono-substituted amino group (for example, anamino group substituted with alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aralkylor heteroaralkyl heterocyclyl(alkyl)), di-substituted amino group (forexample, an amino group substituted with two groups independentlyselected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aralkyl and heteroaralkylheterocyclyl(alkyl)), and protected derivatives thereof (for example,9-fluorenylmethyl carbamate, t-butyl carbamate, benzyl carbamate,acetamide, trifluoroacetamide, phthalimide, benzylamine, triphenylamine,benzylidene amine, and p-toluenesulfonamide).

As used herein, “C_(a)—C_(b)” in which “a” and “b” are integers refer tothe number of carbon atoms in an alkyl, alkenyl or alkynyl group, or thenumber of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl or heterocyclyl group. That is, thealkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of thecycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of theheteroaryl or ring of the heterocyclyl can contain from “a” to “b”,inclusive, carbon atoms. Thus, for example, a “C₁-C₄ alkyl” group refersto all alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.Likewise, for example, a heterocyclyl group may contain from “a” to “b”,inclusive, total atoms, such as a 3 to 10-membered heterocyclyl group,which includes 3 to ten total atoms (carbon and heteroatoms). If no “a”and “b” are designated with regard to an alkyl, alkenyl, alkynyl,cycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heterocyclylgroup, the broadest range described in these definitions is to beassumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, andhexyls. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group, as defined herein,that contains in the straight or branched hydrocarbon chain one or moredouble bonds. An alkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group as defined herein,that contains in the straight or branched hydrocarbon chain one or moretriple bonds. An alkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” and “carbocyclyl” refer to a completelysaturated (no double or triple bonds) mono- or multi-cyclic (such asbicyclic) hydrocarbon ring system. When composed of two or more rings,the rings may be joined together in a fused fashion. Cycloalkyl groupscan contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s).A cycloalkyl group may be unsubstituted or substituted. Typicalcycloalkyl groups include, but are in no way limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclic (suchas bicyclic) hydrocarbon ring system that contains one or more doublebonds in at least one ring; although, if there is more than one, thedouble bonds cannot form a fully delocalized pi-electron systemthroughout all the rings (otherwise the group would be “aryl,” asdefined herein). When composed of two or more rings, the rings may beconnected together in a fused fashion. A cycloalkenyl group may beunsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclic (suchas bicyclic) hydrocarbon ring system that contains one or more triplebonds in at least one ring. If there is more than one triple bond, thetriple bonds cannot form a fully delocalized pi-electron systemthroughout all the rings. When composed of two or more rings, the ringsmay be joined together in a fused fashion. A cycloalkynyl group may beunsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic (such as bicyclic) aromatic ring system (including, e.g.,fused, bridged, or spiro ring systems where two carbocyclic rings sharea chemical bond, e.g., one or more aryl rings with one or more aryl ornon-aryl rings) that has a fully delocalized pi-electron systemthroughout at least one of the rings. The number of carbon atoms in anaryl group can vary. For example, the aryl group can be a C₆-C₁₄ arylgroup, a C₆-C₁₀ aryl group, or a phenyl group. Examples of aryl groupsinclude, but are not limited to, benzene, naphthalene, and azulene. Anaryl group may be substituted or unsubstituted.

As used herein, “cycloalkyl(alkyl)” and “cycloalkyl(alkyl)” refer to acycloalkyl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and cycloalkyl of the cycloalkyl(alkyl) groupcan be substituted or unsubstituted. Examples include but are notlimited to cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl,cyclohexylalkyl, cycloheptylalkyl, and cyclooctylalkyl. When acycloalkyl(alkyl) group is substituted, the substitution can be on thecycloalkyl portion of the cycloalkyl(alkyl) group, the alkyl portion ofthe cycloalkyl(alkyl) group, or on both the cycloalkyl and alkylportions of the cycloalkyl(alkyl) group.

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of aralkyl may be substituted or unsubstituted.Examples include but are not limited to phenyllalkyl (such as benzyl)and naphthylalkyl. An aryl(alkyl) group can be substituted orunsubstituted. When an aryl(alkyl) group is substituted, thesubstitution can be on the aryl portion of the aryl(alkyl) group, thealkyl portion of the aryl(alkyl) group, or on both the aryl and alkylportions of the aryl(alkyl) group.

As used herein, “heteroaryl” refers to a monocyclic or multicyclic (suchas bicyclic) aromatic ring system (a ring system having a least one ringwith a fully delocalized pi-electron system) that contain(s) one or moreheteroatoms, that is, an element other than carbon, including but notlimited to, nitrogen, oxygen, and sulfur, and at least one aromaticring. The number of atoms in the ring(s) of a heteroaryl group can vary.For example, the heteroaryl group can contain 4 to 14 atoms in thering(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).Furthermore, the term “heteroaryl” includes fused ring systems where tworings, such as at least one aryl ring and at least one heteroaryl ring,or at least two heteroaryl rings, share at least one chemical bond.Examples of heteroaryl rings include, but are not limited to, furan,furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole,benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole,benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine,pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,and triazine. A heteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclic” or “heterocyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic, and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system.Heterocyclyl groups may be substituted or unsubstituted. A heterocyclemay optionally contain one or more unsaturated bonds situated in such away, however, that a fully delocalized pi-electron system does not occurthroughout all the rings. The heteroatoms are independently selectedfrom oxygen, sulfur, and nitrogen. A heterocycle may further contain oneor more carbonyl or thiocarbonyl functionalities, so as to make thedefinition include oxo-systems and thio-systems such as lactams,lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Additionally, any nitrogens in a heterocycle may bequaternized. Examples of such “heterocyclic” groups include but are notlimited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane,1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin,1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline,imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine,oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidineN-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione,4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine,tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine,thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fusedanalogs (e.g., benzimidazolidinone, tetrahydroquinoline,3,4-methylenedioxyphenyl).

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fusedanalogs. A heteroaryl(alkyl) group can be substituted or unsubstituted.When a heteroaryl(alkyl) group is substituted, the substitution can beon the heteroaryl portion of the heteroaryl(alkyl) group, the alkylportion of the heteroaryl(alkyl) group, or on both the heteroaryl andalkyl portions of the heteroaryl(alkyl) group.

As used herein, “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” referto a heterocyclic or a heteroalicyclic group connected, as asubstituent, via a lower alkylene group. The lower alkylene andheterocyclyl of a (heteroalicyclyl)alkyl may be substituted orunsubstituted. Examples include but are not limitedtetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl),piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and1,3-thiazinan-4-yl(methyl). A heterocyclyl(alkyl) group can besubstituted or unsubstituted. When a heterocyclyl(alkyl) group issubstituted, the substitution can be on the heterocyclyl portion of theheterocyclyl(alkyl) group, the alkyl portion of the heterocyclyl(alkyl)group, or on both the heterocyclyl and alkyl portions of theheterocyclyl(alkyl) group.

As used herein, “heteroalicyclyl(alkoxy)” and “heterocyclyl(alkoxy)”refer to a heterocyclic or a heteroalicyclic group connected, as asubstituent, via a C₁-C₆ alkoxy group, wherein the heterocyclic or aheteroalicyclic group is connected to a carbon atom of the alkoxy groupvia a carbon atom or a heteroatom of the heterocyclic or aheteroalicyclic group. The C₁-C₆ alkoxy and heterocyclyl of a(heteroalicyclyl)alkoxy may be substituted or unsubstituted. Examplesinclude but are not limited to morpholino(ethoxy),morpholino(n-propoxy), morpholino(n-butoxy), piperidinyl(ethoxy),piperidinyl(n-propoxy), piperidinyl(n-butoxy), piperazinyl(ethoxy),piperazinyl(n-propoxy), and piperazinyl(n-butoxy).

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Lower alkylene groups contain from 1 to 6 carbon atoms. Examplesinclude but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and butylene (—CH₂CH₂CH₂CH₂—). A lower alkylenegroup can be substituted by replacing one or more hydrogen of the loweralkylene group with a substituent(s) listed under the definition of“substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or acycloalkynyl, as defined above. A non-limiting list of alkoxys ismethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl, as defined above, connected, as substituents, via a carbonylgroup. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl.An acyl may be substituted or unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups includebut are not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl, as defined above, such as but not limited to phenyl. Bothan aryloxy and arylthio may be substituted or unsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heterocyclyl, or aralkyl, as definedherein. An O-carboxy may be substituted or unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group wherein Xis a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—”group wherein X is a halogen and R_(A) hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, or (heterocyclyl)alkyl.

The term “amino” as used herein refers to a —NH₂ group.

A “mono-substituted amine” group refers to a “—NHR_(A)” group in whichR_(A) can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl),aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as definedherein. The R_(A) may be substituted or unsubstituted. Amono-substituted amine group may also be referred to as, for example, amono-alkylamine group, a mono-C₁-C₆ alkylamine group, a mono-arylaminegroup, a mono-C₆-C₁₀ arylamine group and the like. Examples ofmono-substituted amino groups include, but are not limited to,—NH(methyl), —NH(phenyl) and the like.

A “di-substituted amine” group refers to a “—NR_(A)R_(B)” group in whichR_(A) and R_(B) can be independently an alkyl, an alkenyl, an alkynyl, acycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl), as defined herein. R_(A) and R_(B) canindependently be substituted or unsubstituted. A di-substituted aminegroup may also be referred to as, for example, a di-alkylamine group, adi-C₁-C₆ alkylamine group, a di-arylamine group, a di-C₆-C₁₀ arylaminegroup and the like. Examples of di-substituted amino groups include, butare not limited to, —N(methyl)₂, —N(phenyl)(methyl), —N(ethyl)(methyl)and the like.

A “dialkylamino(alkyl)” group refers to a “—(C₁-C₆ alkyl)NR_(A)R_(B)”group in which R_(A) and R_(B) can be independently an alkyl, analkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl), as defined herein. R_(A) and R_(B) canindependently be substituted or unsubstituted. A dialkylamino(alkyl)group may also be referred to as, for example, an alkyl(dialkylamino)group. Examples of dialkylamino(alkyl) groups include, but are notlimited to, -ethyl[N(methyl)₂], -ethyl[N(phenyl)(methyl)],-ethyl[N(ethyl)(methyl)], -methyl[N(methyl)₂],-methyl[N(phenyl)(methyl)], -methyl[N(ethyl)(methyl)],-propyl[N(methyl)₂], -propyl[N(phenyl)(methyl)],-propyl[N(ethyl)(methyl)], and the like.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

A “carbonyl” group refers to a C═O group.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, or (heterocyclyl)alkyl, as defined above. A C-amido may besubstituted or unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, or (heterocyclyl)alkyl, as defined above. An N-amido may besubstituted or unsubstituted.

A “urea” group refers to a “N(R_(A)R_(B))C(═O)N(R_(C))—” group in whichR_(A), R_(B), and R_(C) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, or (heterocyclyl)alkyl, as defined above. A ureamay be substituted or unsubstituted.

A “thiourea” group refers to a “N(R_(A)R_(B))C(═S)N(R_(C))—” group inwhich R_(A), R_(B), and R_(C) can be independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, or (heterocyclyl)alkyl, as definedabove. A thiourea may be substituted or unsubstituted.

A “guanidino” group refers to a N(R_(A)R_(B))C(═N)N(R_(C))—” group inwhich R_(A), R_(B), and R_(C) can be independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, or (heterocyclyl)alkyl, as definedabove. A guanidino may be substituted or unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine, and iodine.

In all of the definitions described herein, the terms used to define anew term are as previously defined herein.

Where the numbers of substituents is not specified (e.g., haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two, or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls (e.g., t-butoxycarbonyl(BOC), acetyl, or isobutyryl); arylalkylcarbonyls (e.g.,benzyloxycarbonyl or benzoyl); substituted methyl ether (e.g.,methoxymethyl ether); substituted ethyl ether; a substituted benzylether; tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, ort-butyldiphenylsilyl); esters (e.g., benzoate ester); carbonates (e.g.,methoxymethylcarbonate); sulfonates (e.g., tosylate or mesylate);acyclic ketal (e.g., dimethyl acetal); cyclic ketals (e.g., 1,3-dioxaneor 1,3-dioxolanes); acyclic acetal; cyclic acetal; acyclic hemiacetal;cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or1,3-dithiolane); and triarylmethyl groups (e.g., trityl;monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); or4,4′,4″-trimethoxytrityl (TMTr)).

“Leaving group” as used herein refers to any atom or moiety that iscapable of being displaced by another atom or moiety in a chemicalreaction. More specifically, in some embodiments, “leaving group” refersto the atom or moiety that is displaced in a nucleophilic substitutionreaction. In some embodiments, “leaving groups” are any atoms ormoieties that are conjugate bases of strong acids. Examples of suitableleaving groups include, but are not limited to, tosylates and halogens.Non-limiting characteristics and examples of leaving groups can befound, for example in Organic Chemistry, 2d ed., Francis Carey (1992),pages 328-331; Introduction to Organic Chemistry, 2d ed., AndrewStreitwieser and Clayton Heathcock (1981), pages 169-171; and OrganicChemistry, 5^(th) ed., John McMurry (2000), pages 398 and 408; all ofwhich are incorporated herein by reference for the limited purpose ofdisclosing characteristics and examples of leaving groups.

The term “pharmaceutically acceptable salt” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic acid, acetic acid, propionic acid,glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid,trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid,succinic acid, lactic acid, malic acid, tartaric acid, citric acid,ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonicacid, p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid,butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, 2-naphthalenesulfonic acid, or naphthalenesulfonic acid.Pharmaceutical salts can also be obtained by reacting a compound with abase to form a salt such as an ammonium salt, an alkali metal salt, suchas a lithium, sodium or a potassium salt, an alkaline earth metal salt,such as a calcium, magnesium or aluminum salt, a salt of organic basessuch as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine,dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, tromethamine, and salts with aminoacids such as arginine and lysine; or a salt of an inorganic base, suchas aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, or the like.

Some embodiments provide pharmaceutically acceptable salts of Formula(II). In some embodiments, the salt is selected from hydrochloride,sulfate, hemisulfate, acetate, fumarate, malate, and citrate.

The term “solvate” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to mean that the solvent is complexed with acompound in a reproducible molar ratio, including, but not limited to,0.5:1, 1:1, or 2:1. Thus, the term “pharmaceutically acceptablesolvate,” refers to a solvate wherein the solvent is one that does notcause significant irritation to an organism to which it is administeredand does not abrogate the biological activity and properties of thecompound.

Some embodiments provide solvates of Formula (II). In some embodiments,the solvent in the solvate is selected from water, ethanol, and acetone,or combinations thereof.

The term “prodrug” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a compound or a pharmaceutical compositionthat can be administered to a patient in a less active or inactive form,which can then be metabolized in vivo into a more active metabolite. Incertain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically, ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically, or therapeutically active form ofthe compound.

The term “sunburn” as used herein refers to an acute cutaneousinflammatory reaction following skin exposure to UV radiation. Inhumans, a sunburn may be characterized by red skin that is hot to thetouch, skin pain, general fatigue or malaise, and mild dizziness.

The term “skin hypopigmentation,” as used herein refers to lack or lossof skin color. Hypopigmentation may be caused by depletion ofmelanocytes or melanin, or decreased melanin synthesis. Certaindisorders associated with skin hypopigmentation include, but are notlimited to albinism, idiopathic guttate hypomelanosis, lleucism,phenylketonuria, pityriasis alba, vitiligo, Angelman syndrome, tineaversicolor, and as a side effect of imatinib (Gleeveco) therapy.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, or maybe stereoisomeric mixtures, and include all diastereomeric, andenantiomeric forms. In addition it is understood that, in any compounddescribed herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof. Stereoisomers are obtained,if desired, by methods such as, stereoselective synthesis and/or theseparation of stereoisomers by chiral chromatographic columns.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensand/or deuteriums.

It is understood that the compounds described herein can be labeledisotopically or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. Substitution with isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements. Each chemical element as represented ina compound structure may include any isotope of said element. Forexample, in a compound structure a hydrogen atom may be explicitlydisclosed or understood to be present in the compound. At any positionof the compound that a hydrogen atom may be present, the hydrogen atomcan be any isotope of hydrogen, including but not limited to hydrogen-1(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus,reference herein to a compound encompasses all potential isotopic formsunless the context clearly dictates otherwise.

It is understood that the methods and formulations described hereininclude the use of crystalline forms, amorphous phases, and/orpharmaceutically acceptable salts, solvates, hydrates, and conformers ofcompounds of preferred embodiments, as well as metabolites and activemetabolites of these compounds having the same type of activity. Aconformer is a structure that is a conformational isomer. Conformationalisomerism is the phenomenon of molecules with the same structuralformula but different conformations (conformers) of atoms about arotating bond. In specific embodiments, the compounds described hereinexist in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol, or the like. In other embodiments, the compoundsdescribed herein exist in unsolvated form. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, or the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. In addition, the compounds provided herein can existin unsolvated as well as solvated forms. In general, the solvated formsare considered equivalent to the unsolvated forms for the purposes ofthe compounds and methods provided herein. Other forms in which thecompounds of preferred embodiments can be provided include amorphousforms, milled forms and nano-particulate forms.

Likewise, it is understood that the compounds described herein, such ascompounds of preferred embodiments, include the compound in any of theforms described herein (e.g., pharmaceutically acceptable salts,prodrugs, crystalline forms, amorphous form, solvated forms,enantiomeric forms, tautomeric forms, and the like).

Additional Therapeutic Agents

Suitable additional (or second) therapeutic agents described hereininclude, for example, anti-inflammatory agents, anti-cancer agents,immunostimulatory agents, and immunosuppressive agents. In someembodiments, the second therapeutic agent is an anti-inflammatory agent.In some embodiments, the second therapeutic agent is a non-steroidalanti-inflammatory agent. In some embodiments, the second therapeuticagent is an anti-cancer agent. In some embodiments, the secondtherapeutic agent is an immunostimulatory agent. In some embodiments,the second therapeutic agent is an immunosuppressive agent. In someembodiments, the second therapeutic agent is an antibody.

In some embodiments, the second therapeutic agent is selected fromaspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen;naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen;oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac;ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; piroxicam;meloxicam; tenoxicam; droxicam; lornoxicam; isoxicam; mefenamic acid;meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilides;clonixin; licofelone; dexamethasone; and prednisone.

In some embodiments, the second therapeutic agent is selected frommechlorethamine; cyclophosphamide; melphalan; chlorambucil; ifosfamide;busulfan; N-nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine(CCNU); semustine (MeCCNU); fotemustine; streptozotocin; dacarbazine;mitozolomide; temozolomide; thiotepa; mytomycin; diaziquone (AZQ);cisplatin; carboplatin; and oxaliplatin.

In some embodiments, the second therapeutic agent is selected fromvincristine; vinblastine; vinorelbine; vindesine; vinflunine;paclitaxel; docetaxel; etoposide; teniposide; tofacitinib; ixabepilone;irinotecan; topotecan; camptothecin; doxorubicin; mitoxantrone; andteniposide.

In some embodiments, the second therapeutic agent is selected fromactinomycin; bleomycin; plicamycin; mitomycin; daunorubicin; epirubicin;idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide;methotrexate; 5-fluorouracil; prednisolone; folinic acid; methotrexate;melphalan; capecitabine; mechlorethamine; uramustine; melphalan;chlorambucil; ifosfamide; bendamustine; 6-mercaptopurine; andprocarbazine.

In some embodiments, the second therapeutic agent is selected fromcladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea;nelarabine; cladribine; clofarabine; ytarabine; decitabine; cytarabine;cytarabine liposomal; pralatrexate; floxuridine; fludarabine;colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel;aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed;carmofur; and floxuridine.

In some embodiments, the second therapeutic agent is selected fromazacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan;belotecan; teniposide; aclarubicin; epirubicin; idarubicin; amrubicin;pirarubicin; valrubicin; zorubicin; mitoxantrone; pixantrone;mechlorethamine; chlorambucil; prednimustine; uramustine; estramustine;carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone;thioTEPA; triaziquone; and triethylenemelamine.

In some embodiments, the second therapeutic agent is selected fromnedaplatin; satraplatin; procarbazine; dacarbazine; temozolomide;altretamine; mitobronitol; pipobroman; actinomycin; bleomycin;plicamycin; aminolevulinic acid; methyl aminolevulinate; efaproxiral;talaporfin; temoporfin; verteporfin; alvocidib; seliciclib; palbociclib;bortezomib; carfilzomib; anagrelide; masoprocol; olaparib; belinostat;panobinostat; romidepsin; vorinosta; idelalisib; atrasentan; bexarotene;testolactone; amsacrine; trabectedin; alitretinoin; tretinoin;demecolcine; elsamitrucin; etoglucid; lonidamine; lucanthone;mitoguazone; mitotane; oblimersen; omacetaxine mepesuccinate; anderibulin.

In some embodiments, the second therapeutic agent is selected fromazathioprine; Mycophenolic acid; leflunomide; teriflunomide; tacrolimus;cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide;pomalidomide; thalidomide; anakinra; sirolimus; everolimus;ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab;adalimumab; afelimomab; certolizumab pegol; golimumab; infliximab;nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab;lebrikizumab; ustekinumab; etanercept; otelixizumab; teplizumab;visilizumab; clenoliximab; keliximab; zanolimumab; efalizumab;erlizumab; obinutuzumab; rituximab; and ocrelizumab.

In some embodiments, the second therapeutic agent is selected frompascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab;aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod;ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab;natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab;inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab;maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab;siplizumab; talizumab; telimomab; vapaliximab; vepalimomab; abatacept;belatacept; pegsunercept; aflibercept; alefacept; and rilonacept.

Dosing Regimes

The definitions for compounds of Formula (II) are the same as those setforth above. In some embodiments, the compound of Formula (II) is acompound of Formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), or apharmaceutically acceptable salt thereof.

In some embodiments, about 1 mg to about 5 grams of a compound ofFormula (II) is administered each day. In some embodiments, about 2 mgto about 2 grams of a compound of Formula (II) is administered each day.In some embodiments, the amount of a compound of Formula (II)administered each day is, or is about, 5 mg to 1 gram; 10 mg to 800 mg;20 mg to 600 mg; 30 mg to 400 mg; 40 mg to 200 mg; 50 mg to 100 mg; orany amount in between.

In some embodiments, about 1 mg to about 5 grams of a compound ofFormula (II) is administered each week. In some embodiments, about 2 mgto about 2 grams of a compound of Formula (II) is administered eachweek. In some embodiments, the amount of a compound of Formula (II)administered each week is, or is about, 5 mg to 1 gram; 10 mg to 800 mg;20 mg to 600 mg; 30 mg to 400 mg; 40 mg to 200 mg; 50 mg to 100 mg; orany amount in between.

In some embodiments, about 1 mg to about 5 grams of a compound ofFormula (II) is administered each cycle of treatment. In someembodiments, about 2 mg to about 2 grams of a compound of Formula (II)is administered each cycle of treatment. In some embodiments, the amountof a compound of Formula (II) administered each cycle of treatment is,or is about, 5 mg to 1 gram; 10 mg to 800 mg; 20 mg to 600 mg; 30 mg to400 mg; 40 mg to 200 mg; 50 mg to 100 mg; or any amount in between.

In some embodiments, a compound of Formula (II) is administered at leastonce per day; twice per day; three times per day; or four times per day.In some embodiments, a compound of Formula (II) is administered at leastonce per week; twice per week; three times per week; or four times perweek. In some embodiments, each cycle of treatment lasts 1 day; 2 days;3 days; 4 days; 5 days; 6 days; 7 days; 8 days; 9 days; 10 days; 11days; 12 days; 13 days; 14 days, or any time in between. In someembodiments, each cycle of treatment has at least 1 day; 2 days; 3 days;4 days; 5 days; 6 days; 7 days; 8 days; 9 days; 10 days; 11 days; 12days; 13 days; or 14 days, between administrations of a compound ofFormula (II).

In some embodiments, a compound of Formula (II) is providedintravenously over about 10 minutes; about 20 minutes; about 30 minutes;about 1 h; about 1.5 h; about 2 h; about 2.5 h; about 3 h; about 3.5 h;about 4 h, or any time in between. In some embodiments, the compound ofFormula (II) is a compound of Formula (IIa), (IIb), (IIc), (IId), (IIe)or (IIf), or a pharmaceutically acceptable salt thereof.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Characterization of the compounds disclosed herein was performed withBruker AV-500 and DRX-500 NMR spectrometers and a Perkin Elmer PE-SCIEXAPI-150 mass spectrometer.

Synthesis

Compound 1:(S)-3-(6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione

Methyl 3-methylthiophene-2-carboxylate (1.5 g, 9.60 mmol) was dissolvedin CCl₄ (45 mL). NBS (1.7 g, 9.55 mmol) was added followed by AIBN (0.5mL, 12% in acetone). The mixture was heated at 80° C. for 18 h, followedby workup to provide methyl 3-(bromomethyl)thiophene-2-carboxylate (2.15g, 97%). MS (M+Na) 258.1

Methyl 3-(bromomethyl)thiophene-2-carboxylate (1.0 g, 4.25 mmol) wasdissolved in ACN (12 mL) followed by (S)-3-aminoazepan-2-onehydrochloride (0.700 g, 4.25 mmol) and K₂CO₃ (2.0 g, 14.8 mmol). Thereaction was stirred at rt for 20 h. Following workup, the reaction waspurified on silica gel (EA/MeOH; 90:10) to give methyl(S)-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate (0.300 g,25%). (M+1) 283.3.

Methyl (S)-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate(0.300 g, 1.06 mmol) was dissolved in THF and MeOH. A 1 M solution ofNaOH was added and the reaction was stirred at rt for 18 h, followed byacidification with 1 N HCl and evaporation to a solid. DCM (15 mL) wasadded followed by HOBt (0.244 g, 1.59 mmol), EDCI (0.303 g, 1.59 mmol)and trimethylamine (0.321 g, 3.18 mmol). The mixture was stirred at rtfor 18 h, followed by workup to provide(S)-5-(2-oxoazepan-3-yl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (0.180g, 35%). (M+1) 251.3.

(S)-5-(2-oxoazepan-3-yl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (0.078g, 0.312 mmol) was slurried in ACN with wet DMSO. Dess-Martin reagent(0.27 g, 0.636 mmol, 2.1 eq.) was added and the mixture was stirred at80° C. for 18 h, cooled to rt and worked up. The resulting oil waspurified on silica gel (EA/Hexanes; 1:1 to 100% EA) to provide(S)-3-(6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione(0.020 g, 20%). (M+1) 265.3. 1H NMR (DMSO-d6) δ 10.6 (s, 1H), 8.02 (d,1H), 7.25 (d, 1H), 5.13 (q, 1H), 4.46 (d, 2H), 3.08 (m, 1H), 2.59 (m,1H), 2.23 (m, 1H), 2.12 (m, 1H), 2.09 (m, 1H), 1.82 (m, 1H).

Compound 2:(S)-3-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione

Methyl 2-methylthiophene-3-carboxylate (0.915 g, 5.86 mmol) wasdissolved in CCl₄ (30 mL). NBS (1.04 g, 5.86 mmol) was added followed byAIBN (0.4 mL, 12% in acetone). The mixture was heated at 80° C. for 18h, followed by workup to provide methyl2-(bromomethyl)thiophene-3-carboxylate (1.35 g, 98%). MS (M+1) 236.1.

Methyl 2-(bromomethyl)thiophene-3-carboxylate (1.32 g, 5.62 mmol) wasdissolved in ACN (15 mL) followed by (S)-3-aminoazepan-2-onehydrochloride (0.870 g, 5.62 mmol) and K₂CO₃ (2.6 g, 18.8 mmol). Themixture was stirred at rt for 20 h, followed by workup. The mixture waspurified on silica gel (EA/MeOH; 90:10) to provide methyl(S)-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate (0.557 g,37%). (M+1) 283.3.

Methyl (S)-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(0.557 g, 1.97 mmol) was dissolved in THF and MeOH, followed by additionof 1 M NaOH (6 mL) and the reaction was stirred at rt for 18 h. Thereaction was acidified with 1 N HCl (6 mL) then evaporated to a solid.DCM (35 mL) was added followed by HOBt (0.452 g, 2.96 mmol), EDCI (0.564g, 2.96 mmol) and trimethylamine (0.795 g, 7.88 mmol) and at rt for 18h. The reaction was then worked up with DCM and saturated NaHCO₃ to give(S)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (0.465g, 94%). (M+1) 251.3

(S)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (0.300g, 1.20 mmol) was slurried in ACN (12 mL) with 20 drops of wet DMSO(prepared by adding 2 drops water in 10 mL DMSO). The Dess-Martinperiodinane reagent (1.07 g, 2.52 mmol, 2.1 eq) was added and themixture was stirred at 80° C. for 18 h. Cooled to rt and 10 mL of asaturated sodium thiosulfate solution was added followed by stirring for5 min. The mixture was poured into DCM and washed with 10% aq. sodiumthiosulfate/NaHCO₃ (1:1 mixture) and brine. The compound was purified onsilica gel (EA/Hexanes; 1:1 to EA 100%) to give(S)-3-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione(0.068 g, 22%) as a white solid. (M+1) 265.3. ¹H NMR (DMSO-d₆) δ 10.6(s, 1H), 7.67 (d, 1H), 7.22 (d, 1H), 5.15 (dd, 1H), 4.59 (m, 2H), 3.05(m, 1H), 2.58 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 2.01 (m, 1H), 1.82(m, 1H).

Compound 3:(S)-5-(2,7-dioxoazepan-3-yl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione

Thieno[2,3-c]furan-4,6-dione (0.305 g, 1.98 mmol) was dissolved inacetic acid (7 mL), NaOAc (0.163 g, 1.98 mmol) and(S)-3-aminoazepan-2-one hydrochloride (0.325 g, 1.98 mmol) were added,and the mixture was heated at 110° C. for 18 h. The solvent was removedunder reduced pressure to afford a crude solid followed by stirring inwater for 3 h. Filtration and drying provided(S)-2-((2-oxoazepan-3-yl)carbamoyl)thiophene-3-carboxylic acid (0.140 g,25%). MS (M+1) 283.3.

(S)-2-((2-oxoazepan-3-yl)carbamoyl)thiophene-3-carboxylic acid (0.140 g,0.496 mmol) was slurried in ACN (1 mL) with carbonyldiimidazole (0.170g, 1.04 mmol), and stirred for 72 h. The residue was slurried in ACNwith wet DMSO. Dess-Martin reagent (0.54 g, 1.27 mmol) was added and themixture was stirred at 80° C. for 18 h, cooled to rt and worked up. Thecrude compound was triturated with EA to give(S)-5-(2,7-dioxoazepan-3-yl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(0.020 g, 15%) as a tan solid. (M+Na) 301.2. ¹H NMR (DMSO-d₆) δ 10.8 (s,1H), 8.29 (d, 1H), 7.53 (d, 1H), 5.13 (dd, 1H), 3.10 (m, 1H), 2.57 (m,1H), 2.52 (m, 1H), 2.12 (m, 1H), 1.96 (m, 1H), 1.85 (m, 1H).

Compound 4:(S)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

Methyl 2-methylthiophene-3-carboxylate (0.915 g, 5.86 mmol) wasdissolved in CCl₄ (30 mL), and NBS (1.04 g, 5.86 mmol) and AIBN (0.4 mL,12% in acetone) were added. The mixture was heated at 80° C. for 18 hand then worked up to provide methyl2-(bromomethyl)thiophene-3-carboxylate (1.35 g, 98%). MS (M+1) 236.1.

Methyl 2-(bromomethyl)thiophene-3-carboxylate (1.32 g, 5.62 mmol) wasdissolved in ACN (15 mL) followed by (S)-3-aminoazepan-2-onehydrochloride (0.870 g, 5.62 mmol) and K₂CO₃ (2.6 g, 18.8 mmol). Themixture was stirred at rt for 20 h, worked up, and purified on silicagel (EA/MeOH; 90:10) to give methyl(S)-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate (0.557 g,37%). (M+1) 283.3.

Methyl (S)-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(0.557 g, 1.97 mmol) was dissolved in THF and MeOH, 1 M solution of NaOHwas added (6 mL), and the reaction was stirred at rt for 18 h. Thereaction was acidified with 1 N HCl (6 mL) and evaporated to a solid.DCM (35 mL) was added followed by HOBt (0.452 g, 2.96 mmol), EDCI (0.564g, 2.96 mmol) and trimethylamine (0.795 g, 7.88 mmol). The mixture wasstirred at rt for 18 h, followed by workup to provide(S)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (0.465g, 94%). (M+1) 251.3

Compound 5:(R)-3-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione

Methyl 2-methylthiophene-3-carboxylate (0.915 g, 5.86 mmol) wasdissolved in CCl₄ (30 mL), NBS (1.04 g, 5.86 mmol) and AIBN (0.4 mL, 12%in acetone) were added, and the mixture was heated at 80° C. for 18 h.Workup provided methyl 2-(bromomethyl)thiophene-3-carboxylate (1.35 g,98%). MS (M+1) 236.1.

Methyl 2-(bromomethyl)thiophene-3-carboxylate (1.32 g, 5.62 mmol) wasdissolved in ACN (15 mL) and (R)-3-aminoazepan-2-one hydrochloride(0.870 g, 5.62 mmol) and K₂CO₃ (2.6 g, 18.8 mmol) were added. Themixture was stirred at rt for 20 h, followed by workup and purificationon silica gel (EA/MeOH; 90:10), providing methyl(R)-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate (0.557 g,37%). (M+1) 283.3.

Methyl (R)-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(0.557 g, 1.97 mmol) was dissolved in THF and MeOH, and 1 M NaOH wasadded (6 mL). The reaction was stirred at rt for 18 h, followed byacidification with 1 N HCl (6 mL) and removal of solvent under reducedpressure. DCM (35 mL) was added followed by HOBt (0.452 g, 2.96 mmol),EDCI (0.564 g, 2.96 mmol) and trimethylamine (0.795 g, 7.88 mmol). Themixture was stirred at rt for 18 h. The reaction was then worked up withDCM and saturated NaHCO₃ to give(R)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (0.465g, 94%). (M+1) 251.3

(R)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (0.300g, 1.20 mmol) was slurried in ACN (12 mL) with 20 drops of wet DMSO(prepared by adding 2 drops water in 10 mL DMSO). The Dess-Martinperiodinane reagent (1.07 g, 2.52 mmol, 2.1 eq) was added and themixture was stirred at 80° C. for 18 h. Cooled to rt and 10 mL of asaturated aq. sodium thiosulfate was added. The mixture was poured intoDCM and washed with 10% aq. sodium thiosulfate/NaHCO₃ (1:1 mixture) andbrine. The compound was purified on silica gel (EA/Hexanes; 1:1 to EA100%) to give(R)-3-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione(0.068 g, 22%) as a white solid. (M+1) 265.3. 1H NMR (DMSO-d6) δ 10.6(s, 1H), 7.67 (d, 1H), 7.22 (d, 1H), 5.15 (dd, 1H), 4.59 (m, 2H), 3.05(m, 1H), 2.58 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 2.01 (m, 1H), 1.82(m, 1H).

Compound 6:(S)-3-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)pyrrolidine-2,5-dione

Methyl 2-(bromomethyl)thiophene-3-carboxylate (1.30 g, 5.62 mmol) wasdissolved in ACN (15 mL) followed by (S)-3-aminopyrrolidin-2-one (0.760g, 5.62 mmol) and K₂CO₃ (2.6 g, 18.8 mmol). The mixture was stirred atrt for 20 h. The reaction was worked up with DCM and saturated Na₂CO₃and purified on silica gel (EA/MeOH; 90:10) to give methyl(S)-2-(((2-oxopyrrolidin-3-yl)amino)methyl)thiophene-3-carboxylate(0.281 g, 20%). (M+1) 254.3

Methyl(S)-2-(((2-oxopyrrolidin-3-yl)amino)methyl)thiophene-3-carboxylate(0.281 g, 1.10 mmol) was dissolved in THF and MeOH and a 1 M solution ofNaOH was added (3.5 mL). The reaction was stirred at rt for 18 hfollowed by acidification with 1 N HCl (6 mL) and removal of solventunder reduced pressure. DCM (20 mL) was added followed by HOBt (0.253 g,1.63 mmol), EDCI (0.315 g, 1.63 mmol) and trimethylamine (0.8 mL). Themixture was stirred at rt for 18 h, and worked up to provide(S)-5-(2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(0.079 g, 32%). (M+1) 222.2.

(S)-5-(2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(0.078 g, 0.351 mmol) was slurried in ACN (4 mL) and wet DMSO.Dess-Martin reagent (0.313 g, 2.1 eq) was added and the mixture wasstirred at 80° C. for 18 h, cooled to rt, and worked up. The crudemixture was purified on silica gel (EA/Hexanes; 1:1 to EA 100%) to give(S)-3-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)pyrrolidine-2,5-dione(0.006 g, 7%) as a white solid. (M+1) 236.3. ¹H NMR (DMSO-d₆) δ 11.4 (s,1H), 7.69 (d, 1H), 7.21 (d, 1H), 5.12 (dd, 1H), 4.56 (q, 2H), 2.93 (m,3H).

Compound 7:(S)-3-(4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione

Methyl 4-methylthiophene-3-carboxylate (1.50 g, 9.60 mmol) was dissolvedin CCl₄ (40 mL) and NBS (1.79 g, 10.1 mmol) and dibenzoylperoxide (0.232g, 0.1 eq) were added. The mixture was heated at 80° C. for 4 h andworked up to provide methyl 4-(bromomethyl)thiophene-3-carboxylate (2.2g, 100%). MS (M+1) 236.1.

Methyl 2-(bromomethyl)thiophene-3-carboxylate (2.2 g, 9.36 mmol) wasdissolved in ACN (100 mL) and (S)-3-aminoazepan-2-one hydrochloride(1.53 g, 9.36 mmol) and K₂CO₃ (3.86 g, 27.9 mmol) were added. Themixture was stirred at rt for 18 h, followed by workup and purificationon silica gel (EA/MeOH; 90:10) to give methyl(S)-4-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate (0.308 g,11%). (M+1) 283.3.

Methyl (S)-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(0.310 g, 1.09 mmol) was dissolved in MeOH (10 mL) and a 1 M solution ofNaOH was added (3 mL). The reaction was stirred at rt for 18 h, followedby acidification with 1 N HCl (6 mL) and removal of solvent underreduced pressure. DCM (20 mL) was added followed by HOBt (0.253 g, 1.65mmol), EDCI (0.317 g, 1.65 mmol) and trimethylamine (0.7 mL). Themixture was stirred at rt for 18 h, followed by workup to provide(S)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one (0.230g, 84%). (M+1) 251.3.

(S)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one (0.230g, 0.920 mmol) was slurried in ACN (10 mL) with wet DMSO. Dess-Martinreagent (0.819 g, 2.1 eq) was added and the mixture was stirred at 80°C. for 18 h, cooled to rt and worked up. The crude mixture was purifiedon silica gel (EA/Hexanes; 1:1 to EA 100%) to give(S)-3-(4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione (0.028 g,12%) as a white solid. (M+1) 265.3. ¹H NMR (DMSO-d₆) δ 10.7 (s, 1H),8.03 (d, 1H), 7.50 (d, 1H), 5.14 (dd, 1H), 4.40 (m, 2H), 3.05 (m, 1H),2.54 (m, 1H), 2.21 (m, 1H), 2.08 (m, 1H), 1.96 (m, 1H), 1.80 (m, 1H).

Compound 8:(S)-3-(1-methyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione

Methyl 4-methylthiophene-3-carboxylate (3.62 g, 23.2 mmol) was dissolvedin N,N-dimethylformamide (60 mL), NBS (4.33 g, 24.3 mmol) was added, andthe reaction was stirred at rt for 18 h. The mixture was then worked up,filtered, and dried to give methyl5-bromo-4-methylthiophene-3-carboxylate (4.45 g, 82%). MS (M+Na) 258.1.

Methyl 5-bromo-4-methylthiophene-3-carboxylate (2.16 g, 9.19 mmol) wasdissolved in CCl₄ (60 mL) and NBS (1.72 g, 9.66 mmol) anddibenzoylperoxide (0.1 eq) were added. The mixture was heated at 80° C.for 4 h and worked up to provide methyl5-bromo-4-(bromomethyl)thiophene-3-carboxylate (2.55 g, 89%). MS (M+Na)337.1.

(S)-3-Aminoazepan-2-one (1.1 g, 8.59 mmol) was stirred in ACN (40 mL)and K₂CO₃ (1.35 g, 9.76 mmol) was added, followed up dropwise additionof methyl 5-bromo-4-(bromomethyl)thiophene-3-carboxylate (2.55 g, 8.12mmol) dissolved in 40 mL of ACN, and the mixture was stirred at rt for20 h. Following workup, the crude mixture was purified on silica gel(EA/MeOH; 90:10) to give methyl(S)-5-bromo-4-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(0.84 g, 30%). (M+1) 362.3.

Methyl(S)-5-bromo-4-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(0.84 g, 1.06 mmol) was dissolved in methanol (25 mL), and a 1 Msolution of NaOH was added (8 mL). The reaction was stirred at rt for 18h, followed by acidification with 1 N HCl (8 mL) and removal of solventunder reduced pressure. DCM (40 mL) was added followed by HOBt (0.531 g,3.47 mmol), EDCI (0.667 g, 3.47 mmol) and trimethylamine (0.98 g, 9.70mmol). The mixture was stirred at rt for 48 h, and then worked up toprovide(S)-1-bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.740 g, 97%). (M+1) 330.3.

(S)-1-bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.320 g, 0.973 mmol) was slurried in dioxane (9 mL) and water (3 mL)and methylboronic acid (0.160 g, 2.67 mmol),tetrakis(triphenylphosphine)palladium (0.112 g, 0.097 mmol) and cesiumcarbonate (0.96 g, 2.94 mmol) were added. The reaction was flushed withnitrogen and heated at 90° C. for 18 h. Workup and silica gelpurification provided(S)-1-methyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.103 g, 40%). (M+Na) 352.2.

(S)-1-methyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.13 g, 0.492 mmol) was slurried in ACN (6 mL) with wet and Dess-Martinreagent (0.438 g, 1.032 mmol, 2.1 eq) was added. The mixture was stirredat 80° C. for 18 h, cooled to rt, and worked up. The crude mixture waspurified on silica gel (EA/Hexanes; 1:1 to EA 100%) to give(S)-3-(1-methyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione(0.033 g, 24%) as a yellow solid. (M+23) 301.2. ¹H NMR (DMSO-d₆) δ 10.6(s, 1H), 7.76 (s, 1H), 5.13 (q, 1H), 4.31 (s, 2H), 3.05 (m, 1H), 2.57(m, 1H), 2.41 (s, 3H), 2.20 (m, 1H), 1.99-2.03 (m, 2H), 1.82 (m, 1H).

Compound 9:1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of 3-aminopiperidine-2,6-dione (1.26 g, 7.67 mmol) in DMF(60 mL) at 0° C. was added triethylamine (1.62 g, 15.98 mmol) followedby methyl 5-bromo-4-(bromomethyl)thiophene-3-carboxylate (2.0 g, 6.39mmol). The mixture was warmed to rt and stirred overnight. The mixturewas then concentrated to afford a residue, which was purified on silicagel eluting with EA in petroleum (10% to 100%) to give methyl5-bromo-4-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylateas a purple solid (977 mg, 42.5%). MS (ESI) m/z=361 [M+H]⁺.

To a solution of methyl 5-bromo-4-(((2,6-dioxopiperidin-3-yl)amino)methyl) thiophene-3-carboxylate (892 mg, 2.48 mmol) in THF (20 mL)at 0° C. was added NaOH (1N, 6 mL). The mixture was warmed to rt andstirred overnight. HCl (1N) was then added until a pH of 3-4 wasreached. The mixture was concentrated to give a mixture of5-bromo-4-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylicacid and NaCl as a white solid (858 mg). DMF (20 mL) was added to themixture and cooled 0° C. To this was added HATU (1.41 g, 3.72 mmol) andpyridine (588.5 mg, 7.44 mmol). The mixture was heated to 40° C. andstirred overnight. Additional HATU (1.41 g, 3.72 mmol) and pyridine(588.5 mg, 7.44 mmol) were added to the mixture and stirred at 40° C.for two days. The mixture was then concentrated and the residue waspurified on silica gel eluting with EA in petroleum (10% to 90%) to give3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione asa white solid (415 mg, 55.0%). MS (ESI) m/z=329 [M+H]⁺.

To a solution of3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(370 mg, 1.128 mmol) in anhydrous DMF (11 mL) was added Pd₂(dba)₃ (107.2mg, 0.1128 mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf) (133.6 mg,0.2482 mmol) and Zn(CN)₂ (145.7 mg, 1.241 mmol). The mixture was heatedto 150° C. for 1 h with microwave. The mixture was concentrated and theresidue was purified on silica gel eluting with EA in petroleum (20% to100%) to give5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carbonitrileas a tan solid (88 mg, 45.9%). MS (ESI) m/z=276 [M+H]⁺.

To a solution of5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carbonitrile(88 mg, 0.32 mmol) in tetrahydrofuran (6 mL) was added Raney-Ni (50 mg)and Boc₂O (83.7 mg, 0.384 mmol). The suspension was degassed undervacuum and purged twice with hydrogen. The mixture was stirred at rtovernight. The mixture was then filtered and concentrated. The residuewas purified on silica gel eluting with EA in petroleum (10% to 100%) togive tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamateas a tan solid (32 mg, 26.4%). MS (ESI) m/z=380 [M+H]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(32 mg, 0.08443 mmol) in dichloromethane (2 mL) at 0° C. was added TFA(0.5 mL). The mixture was stirred at rt for 2 h. The mixture was thenconcentrated, diluted with water, and extracted with DCM. The aqueousphase was concentrated to give3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneTFA salt as a yellow solid (23.5 mg, 100%). MS (ESI) m/z=280 [M+H]⁺.

3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneTFA salt (8) (23.5 mg, 0.084 mmol) in THF (3 mL) at rt was added TEA(21.4 mg, 0.211 mmol) followed 2-chloro-4-isocyanato-1-methylbenzene (9)(17 mg, 0.1013 mmol). The mixture was stirred at rt for 1.5 h. Themixture was concentrated and the residue was purified on silica geleluting with MeOH in DCM (0% to 10%) to give1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaas a white solid (19.3 mg, yield: 51.3%). ¹H NMR (400 MHz, DMSO-d₆) δ10.99 (s, 1H), 8.77 (s, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.20-7.13 (m,2H), 6.84 (t, J=6.0, 1H), 5.04-5.0 (m, 1H), 4.43 (d, J=5.6, 2H), 4.28(dd, J=15.2, 42.8, 2H), 2.94-2.85 (m, 1H), 2.61 (s, 1H), 2.35-2.29 (m,1H), 2.24 (s, 3H), 2.02-1.99 (m, 1H). MS (ESI) m/z=447 [M+H]⁺.

Compound 10:(S)-3-(1-Cyclopentyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione

To a solution of(S)-1-bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(250 mg, 0.7622 mmol) in toluene/water (10 mL/1 mL) was addedcyclopent-1-en-1-ylboronic acid (128 mg, 1.143 mmol) and K₂CO₃ (263 mg,1.906 mmol). Following an N₂ purge,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)[Pd(dppf)Cl₂] (112 mg, 0.152 mmol) was added. The suspension was heatedto 100° C., stirred overnight then cooled to RT and concentrated undervacuum. The residue was diluted in water and extracted with DCM (×2).The organic layers were concentrated and the residue purified on silicagel eluting with EA in petroleum (0% to 10%) to give(S)-1-(cyclopent-1-en-1-yl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(145 mg, 60.2%) as a white solid. MS (ESI) m/z=317 [M+H]⁺.

To a solution of(S)-1-(cyclopent-1-en-1-yl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(145 mg, 0.4589 mmol) in THF (5 mL) at RT was added Pd/C (80 mg). Thesuspension was stirred at RT overnight then filtered, and the filtratewas concentrated to give(S)-1-cyclopentyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(136 mg, 93.2%) as a yellow solid. MS (ESI) m/z=319 [M+H]⁺.

To a solution of(S)-1-cyclopentyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(136 mg, 0.4277 mmol) in fluorobenzene (4 mL) with 0.4 mL wet dimethylsulfoxide at 0° C. was added Dess-Martin (544.2 mg, 1.283 mmol). Thesuspension was heated to 80° C. and stirred overnight. The mixture wascooled to RT and 5 mL of sat. sodium thiosulfate was added followed bystirring for 5 min. The mixture was extracted with DCM (15 mL×2) and thecombined extracts were washed with 10% aq. sodium thiosulfate/aq. NaHCO₃(1:1 mixture) (20 mL) and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated to afford the crude product, whichwas purified by prep-TLC (EA) to give(S)-3-(1-cyclopentyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione(5.2 mg, 3.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (s,1H), 7.80 (s, 1H), 5.14 (d, J=12.8 Hz, 1H), 4.42-4.34 (m, 2H), 3.28-3.26(m, 2H), 2.60 (s, 1H), 2.23-2.00 (m, 5H), 1.77 (s, 2H), 1.64-1.62 (m,5H). MS (ESI) m/z 333 [M+H]+.

Compound 11:(S)-3-(2-Methyl-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione

Methyl 2-methylthiophene-3-carboxylate (4.62 g, 29.6 mmol) was dissolvedin DMF (23 mL) and AcOH (15 mL). N-Bromosuccinimide (5.54 g, 29.6 mmol)was added and the reaction was stirred at RT for 18 h. The mixture wasevaporated to dryness then dissolved in EA and washed with sat. aq.NaHCO₃ to give methyl 5-bromo-2-methylthiophene-3-carboxylate (4.90 g,70%) as an orange oil. MS (M+1) 236.1.

5-Bromo-2-methylthiophene-3-carboxylate (4.90 g, 20.8 mmol) wasdissolved in carbon tetrachloride (75 mL). N-Bromosuccinimide (3.90 g,20.9 mmol) was added followed by the addition of dibenzoylperoxide (0.1eq). The mixture was heated at 80° C. for 18 h then cooled to RT. DCMwas added and the solution was washed with sat. aq. NaHCO₃ The organiclayer was concentrated to give methyl5-bromo-2-(bromomethyl)thiophene-3-carboxylate (5.49 g, 84%). MS (M+1)315.1.

(S)-3-Aminoazepan-2-one hydrochloride (2.9 g, 17.7 mmol) was stirred inACN (75 mL) and followed by K₂CO₃ (8.00 g, 57.9 mmol). Methyl5-bromo-2-(bromomethyl)thiophene-3-carboxylate (5.49 g, 17.5 mmol)dissolved in 75 mL of ACN was added dropwise and the mixture was stirredat RT for 20 h. The reaction was concentrated under vacuum and EA wasadded. The solution was washed with sat. aq. NaHCO₃. The organic layerwas dried under vacuum then triturated with EA to give methyl(S)-5-bromo-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(2.97 g, 47%). MS (M+1) 362.3.

Methyl(S)-5-bromo-2-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(2.97 g, 8.22 mmol) was dissolved in MeOH (90 mL). A 1 M solution ofNaOH was added (28 mL) and the reaction was stirred at RT for 18 h. Thereaction was acidified with 1 N HCl (28 mL) then evaporated to a solid.DCM (140 mL) was added followed by HOBt (1.67 g, 12.4 mmol), EDCI (2.37g, 12.4 mmol) and trimethylamine (5 mL). The mixture was stirred at RTfor 48 h. The reaction was then worked up with DCM and sat. aq. NaHCO₃to give(S)-2-bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(2.70 g, 100%). MS (M+1) 330.3.

(S)-2-Bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(0.600 g, 1.82 mmol) was slurried in dioxane (17 mL) and water (6 mL)followed by the addition of methylboronic acid (0.300 g, 5.00 mmol),tetrakis(triphenylphosphine)palladium (0.210 g, 0.182 mmol) and cesiumcarbonate (1.80 g, 5.51 mmol). The reaction was flushed with nitrogenthen heated at 90° C. for 18 h. The reaction was worked up with EA andwater followed on silica gel to give(S)-2-methyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(0.180 g, 37%). MS (M+1) 265.3.

(S)-2-Methyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(0.18 g, 0.682 mmol) was slurried in ACN (9 mL) with 12 drops of wetDMSO (prepared by adding 2 drops water in 10 ml DMSO). The Dess-Martinperiodinane reagent (0.607 g, 1.43 mmol, 2.1 eq) was added and themixture was stirred at 80° C. for 18 h. After cooling to RT, 5 mL of asaturated sodium thiosulfate solution was added followed by stirring for5 min. The mixture was poured into DCM and washed with 10% aq. sodiumthiosulfate/aq. NaHCO₃ (1:1 mixture) then brine. The compound waspurified on silica gel (EA) to give(S)-3-(2-methyl-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione(0.050 g, 40%) as an off white solid. MS (M+23) 301.2. 1H NMR (DMSO-d6)δ 10.6 (s, 1H), 6.92 (s, 1H), 5.12 (q, 1H), 4.53 (s, 2H), 3.04 (m, 1H),2.57 (m, 1H), 2.49 (s, 3H), 2.19 (m, 1H), 1.99-2.03 (m, 2H), 1.80 (m,1H).

Compound 12:(S)-3-(1-Isopropyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione

(S)-1-Bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.430 g, 1.31 mmol) was slurried in dioxane (12 mL) and water (4 mL)followed by the addition of isopropenyl boronic pinacol ester (0.550 g,2.62 mmol), tetrakis(triphenylphosphine)palladium (0.150 g, 0.130 mmol)and cesium carbonate (1.29 g, 3.95 mmol). The reaction was flushed withnitrogen then heated at 90° C. for 18 h. The reaction was cooled to RTthen EA and water was added. The organic phase was concentrated andpurified on silica gel to give(S)-5-(2-oxoazepan-3-yl)-1-(prop-1-en-2-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.236 g, 62%). MS (M+1) 291.3.

(S)-5-(2-Oxoazepan-3-yl)-1-(prop-1-en-2-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.227 g, 0.783 mmol) was dissolved in MeOH (20 mL) followed by theaddition of a catalytic amount of Pd—C. The reaction was stirred underhydrogen gas for 18 h. The reaction was filtered through celite thenconcentrated to give(S)-1-isopropyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.215 g, 94%).

(S)-1-Isopropyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.214 g, 0.732 mmol) was slurried in ACN (11 mL) with 14 drops of wetDMSO (prepared by adding 2 drops water in 10 ml DMSO). The Dess-Martinperiodinane reagent (0.653 g, 1.53 mmol, 2.1 eq) was added and themixture was stirred at 80° C. for 18 h. After cooling to RT, 5 mL of asaturated sodium thiosulfate solution was added followed by stirring for5 min. The mixture was poured into DCM and washed with 10% aq. sodiumthiosulfate/aq. NaHCO₃ (1:1 mixture) then brine. The compound waspurified on silica gel (EA) to give(S)-3-(1-isopropyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione(0.023 g, 10%) as an off white solid. MS (M+23) 329.3.

Compound 13:(S)-3-(1-Bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione

(S)-1-Bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(0.15 g, 0.456 mmol) was slurried in ACN (6 mL) with 8 drops of wet DMSO(prepared by adding 2 drops water in 10 ml DMSO). The Dess-Martinperiodinane reagent (0.406 g, 0.957 mmol, 2.1 eq) was added and themixture was stirred at 80° C. for 18 h. After cooling to RT, 5 mL of asaturated sodium thiosulfate solution was added followed by stirring for5 min. The mixture was poured into DCM and washed with 10% aq. sodiumthiosulfate/aq. NaHCO₃ (1:1 mixture) then brine. The compound waspurified on silica gel (EA) to give(S)-3-(i-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione(0.013 g, 8%) as an off white solid. MS (M+1) 344.2. ¹H NMR (DMSO-d6) δ10.7 (s, 1H), 8.10 (s, 1H), 5.15 (d, 1H), 4.32 (q, 2H), 3.05 (m, 1H),2.55 (m, 1H), 2.24 (m, 1H), 1.99-2.08 (m, 2H), 1.80 (m, 1H).

Compound 14:(S)-3-(2-Bromo-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione

(S)-2-Bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one(0.30 g, 0.912 mmol) was slurried in ACN (12 mL) with 16 drops of wetDMSO (prepared by adding 2 drops water in 10 ml DMSO). The Dess-Martinperiodinane reagent (0.812 g, 1.91 mmol, 2.1 eq) was added and themixture was stirred at 80° C. for 18 h. After cooling to RT, 5 mL of asaturated sodium thiosulfate solution was added followed by stirring for5 min. The mixture was poured into DCM and washed with 10% aq. sodiumthiosulfate/aq. NaHCO₃ (1:1 mixture) then brine. The compound waspurified on silica gel (EA) to give(S)-3-(2-bromo-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)azepane-2,7-dione(0.035 g, 12%) as an off white solid. MS (M+1) 344.2. ¹H NMR (DMSO-d6) δ10.7 (s, 1H), 7.29 (s, 1H), 5.15 (d, 1H), 4.32 (q, 2H), 3.05 (m, 1H),2.55 (m, 1H), 2.24 (m, 1H), 1.99-2.08 (m, 2H), 1.80 (m, 1H).

Compound 15:(S)-5-(2,7-Dioxoazepan-3-yl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione

1H,3H-Thieno[3,4-c]furan-1,3-dione (2.48 g, 16.1 mmol) was dissolved inTHF (150 mL) followed by the addition of (S)-3-aminoazepan-2-one HCl(2.64 g, 16.1 mmol) and trimethylamine (3 mL). The mixture was stirredat RT for 18 h. Carbonyldiimidazole (3.13 g, 19.3 mmol) was added andthe reaction was heated at 64° C. for 2 h. Standard workup with DCM andwater gave(S)-5-(2-oxoazepan-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (3.78 g,89%). MS (M+1) 265.3.

(S)-5-(2-Oxoazepan-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (1.38 g,5.22 mmol) was dissolved in 6 mL of sulfuric acid. The reaction wascooled to 0° C. followed by the addition of fuming nitric acid (3 mL)dissolved in sulfuric acid (2 mL). The mixture was stirred for 1 h at 0°C. then poured into 200 mL of an ice-water mixture. The resultant solidwas filtered and washed with water to give(S)-1-nitro-5-(2-oxoazepan-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(0.485 g, 30%). MS (M+1) 310.2.

(S)-1-Nitro-5-(2-oxoazepan-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(0.485 g, 1.57 mmol) was slurried in ACN (25 mL) with 31 drops of wetDMSO (prepared by adding 2 drops water in 10 ml DMSO). The Dess-Martinperiodinane reagent (1.40 g, 3.30 mmol, 2.1 eq) was added and themixture was stirred at 80° C. for 18 h. After cooling to RT, 5 mL of asaturated sodium thiosulfate solution was added followed by stirring for5 min. The mixture was poured into DCM and washed with 10% aq. sodiumthiosulfate/aq. NaHCO₃ (1:1 mixture) then brine. The compound wastriturated with EA to give(S)-5-(2,7-dioxoazepan-3-yl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(0.150 g, 30%). MS (M+1) 324.3.

Compound 16:(S)-1-Amino-5-(2,7-dioxoazepan-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione

(S)-5-(2,7-Dioxoazepan-3-yl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(0.018 g, 0.056 mmol) was dissolved in MeOH (10 mL) followed by theaddition of a catalytic amount of platinum 1% and vanadium 2%, onactivated carbon (50-70% wetted powder). The reaction was stirred underhydrogen gas for 3 h then filtered through celite. The solvent wasevaporated to give(S)-1-amino-5-(2,7-dioxoazepan-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(0.010 g, 70% purity). MS (M+1) 294.3.

Compound 17:(S)-5-(2,7-Dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carbonitrile

To a solution of methyl 4-methylthiophene-3-carboxylate (20.0 g, 128.1mmol) in DMF (250 mL) at 0° C. was added N-bromosuccinimide (NBS) (23.9g, 134.2 mmol). The mixture was warmed to RT and stirred overnight. Themixture was diluted in ice-water and stirred for 15 minutes. It was thenfiltered, and the cake was washed with water and dried under vacuum togive methyl 5-bromo-4-methylthiophene-3-carboxylate (28.1 g, 93.6%) as ayellow solid.

To a solution of methyl 5-bromo-4-methylthiophene-3-carboxylate (28.1 g,120.1 mmol) in carbon tetrachloride (80 mL) at RT was addedN-bromosuccinimide (NBS) (25.6 g, 143.8 mmol) and dibenzoyl peroxide(BPO) (2.9 g, 11.9 mmol). The mixture was heated to 85° C. for 5 h. Itwas filtered and the filtrate was purified on silica gel eluting with EAin petroleum (0% to 6%) to give methyl5-bromo-4-(bromomethyl)thiophene-3-carboxylate (26.3 g, 70.1%) as awhite solid.

To a solution of (S)-3-aminoazepan-2-one (5.75 g, 44.94 mmol) in DMF(200 mL) at 0° C. was added TEA (7.61 g, 74.91 mmol) and methyl5-bromo-4-(bromomethyl)thiophene-3-carboxylate (11.68 g, 37.45 mmol).The mixture was warmed to RT for 2 h. The mixture was concentrated andthe residue was purified on silica gel eluting with EA in petroleum (0%to 100%) to give methyl(S)-5-bromo-4-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(9.21 g, 68%) as white solid. MS (ESI) m/z=361 [M+H]⁺.

To a solution of methyl(S)-5-bromo-4-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(9.2 g, 25.5 mmol) in ACN (300 mL) was added trimethylaluminium (153 mL,1 M in toluene) at 0° C. A saturated solution of ammonium chloride (20mL) was added dropwise into the mixture at 0° C., then the mixture wasextracted with DCM (200 mL×2). The combined organic layers were washedwith water, dried over Na₂SO₄, filtered, and concentrated to give thecrude product, which was purified on silica gel eluting with EA inpetroleum (1:1) to give(S)-1-bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(7.04 g, 85%) as white solid. MS (ESI) m/z=329, 331 [M+H]⁺.

To a solution of(S)-1-bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(1.1 g, 3.35 mmol) in DMF (12 mL) was added zinc cyanide (394 mg, 3.69mmol), tris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] (323 mg,0.34 mmol) and 1,1′-bisdiphenylphosphinoferrocene [dppf] (396 mg, 0.74mmol). The mixture was heated to 150° C. for 1 h by microwave. Thesolvent was removed under vacuum. The residue was purified on silica geleluting with EA:MeOH (from 0% to 10%) to afford(S)-4-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carbonitrile(700 mg, 84%) as yellow solid. MS (ESI) m/z=276 [M+H]⁺.

To a solution of(S)-4-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carbonitrile(5.2 g, 18.9 mmol) in ACN (120 mL) and wet dimethyl sulfoxide (20 mL)was added Dess-Martin (19.9 g, 47.3 mmol). The mixture was heated to 80°C. and stirred for 6 h. After cooling to RT, a saturated sodiumthiosulfate solution was added followed by stirring for 5 min. Themixture was extracted with DCM (150 mL×2) and the combined solution waswashed with 10% aq. sodium thiosulfate/aq. NaHCO₃ (1:1 mixture) (200 mL)then brine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to afford the crude product. It was purified on silica geleluting with DCM/MeOH (30:1) to give(S)-5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carbonitrile(3.3 g, 61.1%) as yellow solid. MS (ESI) m/z=290 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.77 (s, 1H), 8.55 (s, 1H), 5.18-5.15 (m, 1H), 4.64(dd, J=18.8, 38.8, 2H), 3.07-3.02 (m, 1H), 2.58 (s, 1H), 2.45 (s, 1H),2.10-2.01 (m, 2H), 1.82 (s, 1H).

Compound 18:(S)-3-(1-(Aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoroacetic acid salt

To a solution ofthe(S)-5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-carbonitrile(3.3 g, 11.42 mmol) in THF (100 mL) was added di-t-butyl-dicarbonate(Boc)₂O (4.78 g, 22.84 mmol), Raney-Ni (1 g). Then the suspension wasstirred under hydrogen atmosphere for 10 h at RT. It was filtered andthe filtrated was concentrated to give the crude product. The residuewas purified on silica gel eluting with EA in petroleum (20% to 100%) togive tert-butyl(S)—((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(2.57 g, 57.2%) as a yellow solid. MS (ESI) m/z=394 [M+H]⁺.

To a solution of tert-butyl(S)—((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(35 mg, 0.08906 mmol) in DCM (2 mL) at 0° C. was added2,2,2-trifluoroacetic acid (0.5 mL). The mixture was warmed to RT andstirred for 1.5 h. The reaction was concentrated to remove the solventand the residue was diluted in water. It was extracted with DCM. Theaqueous phase was lyophilized to afford(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoroacetic acid salt (10.8 mg) as a tan solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.77 (s, 1H), 8.26 (s, 3H), 8.11 (s, 1H), 5.20-5.16 (m,1H), 4.48 (dd, J=14.0, 18.8, 2H), 4.27 (s, 2H), 3.11-3.04 (m, 1H), 2.59(s, 1H), 2.18-1.99 (m, 3H), 1.85-1.81 (m, 1H). MS (ESI) m/z 294 [M+H]⁺.

Compound 19:(S)-3-(1-(Difluoromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione

To a solution of methyl 5-bromo-4-methylthiophene-3-carboxylate (3.0 g,12.8 mmol) in DMF (30 mL) was added zinc cyanide (4.51 g, 38.4 mmol),tris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] (580 mg, 0.60mmol), 1,1′-bisdiphenylphosphinoferrocene [dppf] (760 mg, 0.14 mmol) atRT. The mixture was stirred at 150° C. for 1 h in a microwave under N₂.The suspension was filtered and concentrated in vacuo to get the crudeproduct, which was purified on silica gel eluting with (petroleumether/EA=50/1 to 20/1) to afford methyl5-cyano-4-methylthiophene-3-carboxylate (1.20 g, 52%) as a yellow solid.¹H NMR (300 MHz, CDCl₃) δ 8.28 (s, 1H), 3.90 (s, 3H), 2.67 (s, 3H). MS(ESI) m/z 182.0 [M+H]⁺.

To a solution of methyl 5-cyano-4-methylthiophene-3-carboxylate (900 mg,4.97 mmol) and sodium hypophosphite in water/pyridine/AcOH=1/2/1 (5mL/10 mL/5 mL) was added Raney-Ni (100 mg). The mixture was stirred atRT overnight. After the reaction was complete, the solvent was removedunder vacuum and water was added, the mixture was extracted with DCM(100 mL×2), washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford the crude product, which was purified onsilica gel eluting with petroleum ether/EA=100/1 to 80/1 to 60/1 toafford methyl 5-formyl-4-methylthiophene-3-carboxylate (410 mg, 44%) asa yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 10.13 (s, 1H), 8.43 (s, 1H),3.90 (s, 3H), 2.82 (s, 3H). MS (ESI) m/z 185.0 [M+H]⁺.

Methyl 5-formyl-4-methylthiophene-3-carboxylate (410 mg, 2.23 mmol) inDCM (10 mL) was cooled to 0° C., diethylaminosulfur trifluoride (DAST)(1.8 g, 11.14 mmol) was added dropwise. The mixture was stirred at RTovernight under nitrogen atmosphere. The reaction was quenched withNaHCO₃ (aq) at 0° C., then the mixture was extracted with DCM, washedwith brine (120 mL), dried over Na₂SO₄, filtered and concentrated invacuo to afford the crude product, which was purified on silica geleluting with petroleum ether/EA=100/1 to 80/1 to 70/1 to get methyl5-(difluoromethyl)-4-methylthiophene-3-carboxylate (340 mg, 74%) as ared oil. ¹H NMR (300 MHz, CDCl₃) δ 8.19 (s, 1H), 6.91 (t, J=55.5 Hz,1H), 3.88 (s, 3H), 2.53 (s, 3H).

To a solution of methyl5-(difluoromethyl)-4-methylthiophene-3-carboxylate (340 mg, 1.65 mmol)in carbon tetrachloride (6 mL) at RT was added N-bromosuccinimide (NBS)(440 mg, 2.47 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN) (172mg, 0.66 mmol). The suspension was stirred at 90° C. overnight. Afterthe reaction was complete, the solvent was removed under vacuum to getthe crude methyl4-(bromomethyl)-5-(difluoromethyl)thiophene-3-carboxylate (540 mg) as ayellow oil, which was used in the next step without purification. ¹H NMR(300 MHz, CDCl₃) δ 8.23 (s, 1H), 6.91 (t, J=55.5 Hz, 1H), 4.92 (s, 2H),3.93 (s, 3H).

To a solution of methyl4-(bromomethyl)-5-(difluoromethyl)thiophene-3-carboxylate (540 mg, 1.65mmol) in DMF (5 mL) was added TEA (333 mg, 3.3 mmol) and(S)-3-aminoazepan-2-one (253 mg, 1.98 mmol). The mixture was stirred at50° C. for 2 h. After the reaction was complete, the solvent was removedunder vacuum to get the crude product, which was purified on silica geleluting with petroleum ether/EA=2/1 to DCM/MeOH=50/1 to get methyl(S)-5-(difluoromethyl)-4-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate (310 mg, 56%) as a yellow solid. MS (ESI) m/z333.0 [M+H]⁺.

Trimethylaluminium (4.8 mL, 9.6 mmol) was added into a solution of(S)-5-(difluoromethyl)-4-(((2-oxoazepan-3-yl)amino)methyl)thiophene-3-carboxylate(310 mg, 0.96 mmol) in ACN (10 mL) at 0° C. The mixture was stirred atRT for 5 h under nitrogen atmosphere. The mixture was quenched withammonium chloride (aq) at 0° C., then the mixture was extracted with DCM(80 mL×2), washed with brine (70 mL), over Na₂SO₄, and concentrated invacuo to get the crude product, which was purified on silica gel(DCM/MeOH=100/1 to 50/1) to get(S)-1-(difluoromethyl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(160 mg, 55%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.83 (s, 1H),7.03 (t, J=71.4 Hz, 1H), 5.93 (s, 1H), 5.31-5.12 (m, 1H), 4.95 (d, J=6.3Hz, 1H), 4.37 (d, J=16.2 Hz, 1H), 3.45-3.40 (m, 1H), 3.30-3.27 (m, 1H),2.17-2.11 (m, 1H), 1.98-1.82 (m, 3H), 1.74-1.61 (m, 1H), 1.52-1.47 (m,1H). MS (ESI) m/z 301.0 [M+H]^(+.)

To a solution of(S)-1-(difluoromethyl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(160 mg, 0.53 mmol) in fluorobenzene/dimethyl sulfoxide (6 mL/0.6 mL) atRT was added Dess-Martin periodinane (564 mg, 1.33 mmol). The mixturewas stirred at 80° C. overnight. The mixture was cooled to RT and 20 mLof sat. aq. sodium thiosulfate was added followed by stirring for 5 min.The mixture was extracted with DCM (30 mL×2) and the combined solutionwas washed with 10% aq. sodium thiosulfate/aq. NaHCO₃ (1:1 mixture) (50mL) then brine (50 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated to afford the crude product. The crude productwas purified by reverse-LC to afford(S)-3-(1-(difluoromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione(74 mg, 44%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (s,1H), 8.22 (s, 1H), 7.32 (t, J=55.6 Hz, 1H), 5.11-5.07 (m, 1H), 4.47 (s,2H), 2.99 (t, J=13.2 Hz, 1H), 2.42 (s, 1H), 2.13 (s, 1H), 2.04-1.93 (m,2H), 1.73 (s, 1H). MS (ESI) m/z 315.0 [M+H]⁺.

Compound 20: (S)-3-(1-Methyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)pyrrolidine-2,5-dione

To a solution of (tert-butoxycarbonyl)-L-asparagine (2.0 g, 8.61 mmol)in DMF (20 mL) was added 1-hydroxypyrrolidine-2,5-dione (HOSU) (988 mg,8.61 mmol) and dicyclohexylcarbodiimide (DCC) (886 mg, 8.61 mmol). Themixture was stirred at 80° C. for 10 h. The solvent was removed and theresidue was diluted with EA (40 mL). The solid was filtered and thefiltrate was washed with water, dried over Na₂SO₄, filtered, andconcentrated to give the crude product, which was purified on silica geleluting with EA in petroleum (10% to 60%) to give tert-butyl(S)—(2,5-dioxopyrrolidin-3-yl)carbamate (775 mg, 42.1%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz) δ: 11.18 (s, 1H), 7.44 (d, J=8.4 Hz, 1H),4.32-4.26 (m, 1H), 2.87-2.82 (m, 1H), 2.47-2.41 (m, 1H), 1.37 (s, 9H).

To a solution of tert-butyl (S)—(2,5-dioxopyrrolidin-3-yl)carbamate (675mg, 3.153 mmol) in DCM (26 mL) at 0° C. was added TFA (8 mL). Themixture was stirred at RT for 3.5 h. The solvent was removed and theresidue was dried in vacuo to give the crude(S)-3-aminopyrrolidine-2,5-dione (359.7 mg, 100%) as a yellow oil. MS(ESI) m/z=115.1 [M+H]⁺.

To a solution of (S)-3-aminopyrrolidine-2,5-dione (3) (359.7 mg, 3.153mmol) in DMF (26 mL) at 0° C. was added methyl5-bromo-4-(bromomethyl)thiophene-3-carboxylate (820 mg, 2.63 mmol) andTEA (664.6 mg, 6.568 mmol). The mixture was stirred at RT for 16 h. Thesolvent was removed and the residue was purified on silica gel elutingwith EA in petroleum (10% to 100%) to give methyl(S)-5-bromo-4-(((2,5-dioxopyrrolidin-3-yl)amino)methyl)thiophene-3-carboxylate(584 mg, 64.2%) as a yellow solid.

To a solution of methyl(S)-5-bromo-4-(((2,5-dioxopyrrolidin-3-yl)amino)methyl)thiophene-3-carboxylate(450 mg, 1.3 mmol) in THF (10 mL) was added NaOH (1M, 3.2 mL). Themixture was stirred at RT overnight. The mixture was adjusted to pH=5with 2 N HCl then the solvent was removed and the residue was dried invacuo to give the crude(S)-5-bromo-4-(((2,5-dioxopyrrolidin-3-yl)amino)methyl)thiophene-3-carboxylicacid (432 mg, 100%), which was used directly for the next step.

To a solution of(S)-5-bromo-4-(((2,5-dioxopyrrolidin-3-yl)amino)methyl)thiophene-3-carboxylicacid (431 mg, 1.3 mmol) in DMF (15 mL) at 0° C. was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) (988 mg, 2.6 mmol) andN,N-diisopropylethylamine (419.3 mg, 3.25 mmol). The mixture was stirredat RT for 16 h. The reaction was diluted with water (10 mL) andextracted with EA (30 mL×3). The combined organic layers were washedwith water (30 mL), dried over Na₂SO₄, filtered, and concentrated togive crude product, which was purified on silica gel eluting with EA inpetroleum (30% to 50%) to give(S)-3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)pyrrolidine-2,5-dione(238 mg, 58.3%) as a light-yellow solid.

To a solution of(S)-3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)pyrrolidine-2,5-dione(226 mg, 0.719 mmol) in DMF (10 mL) was added K₂CO₃ (166 mg, 0.144mmol). It was degassed and purged with NITROGEN twice. Thentetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄) (297.6 mg, 2.16 mmol)and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (906.3 mg, 3.59 mmol)were added. The suspension was heated to 130° C. and stirred for 16 h.The solvent was removed and the residue was purified by prep-TLC(petroleum ether: EA=1:2) to afford crude product (45 mg), which wasfurther purified by prep-HPLC with 5% to 95% ACN in 0.02% NH₄Ac on aC18, 4.6×50 mm column to give(S)-3-(1-methyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)pyrrolidine-2,5-dione (5.1 mg, 2.8%) as a white solid. ¹H NMR (DMSO-d₆,400 MHz) δ: 11.23 (s, 1H), 7.78 (s, 1H), 5.12 (dd, J=6.4, 9.6 Hz, 1H),4.27 (dd, J=15.2, 108.8 Hz, 2H), 2.98-2.82 (m, 2H), 2.39 (s, 3H). MS(ESI) m/z=250.9 [M+H]⁺.

Compound 21:3-(4-Oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

To a solution of methyl 2-methylthiophene-3-carboxylate (1.9 g, 12.16mmol) in carbon tetrachloride (50 mL) at RT was added N-bromosuccinimide(NBS) (2.6 g, 14.6 mmol). The mixture was heated to 85° C. for 5 minutesand azodiisobutyronitrile (AIBN) (1.05 g, 6.08 mmol) was added in themixture. The mixture was stirred at 85° C. overnight. It was filteredand the filtrate was concentrated. The residue was purified on silicagel eluting with EA in petroleum (0% to 10%) to give methyl2-(bromomethyl)thiophene-3-carboxylate (660 mg, 23.5%) as a yellow oil.

To a solution of 3-aminopiperidine-2,6-dione hydrochloride acid salt(696.3 mg, 4.23 mmol) in DMF (15 mL) at 0° C. was added TEA (713.4 mg,7.05 mmol) and methyl 2—(bromomethyl)thiophene-3-carboxylate (660 mg,2.82 mmol). The mixture was stirred at RT overnight. The mixture wasconcentrated to remove the solvent and the residue was purified onsilica gel eluting with MeOH in DCM (0% to 10%) to give methyl2-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylate (195mg, 24.5%) as a green solid. MS (ESI) m/z=283 [M+H]⁺.

To a solution of methyl2-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylate (195mg, 0.6914 mmol) in THF (10 mL) at 0° C. was added NaOH (1 M, 1.7 mL).The mixture was stirred at RT for 2 h. The mixture was adjusted by HCl(2 N) to pH 3-4. It was then concentrated to afford crude2-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylic acid(185.3 mg, 100%) as a yellow solid.

To a solution of2-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylic acid(185.3 mg, 0.6914 mmol) in DMF (10 mL) at 0° C. was added1-hydroxybenzotriazole (HOBt) (143.1 mg, 1.037 mmol),3-(ethyliminomethylideneamino)—N,N-dimethylpropan-1-amine, hydrochloride(EDCI) (199.1 mg, 1.037 mmol) and TEA (175 mg, 1.729 mmol). The mixturewas stirred at RT overnight. After removing the solvent under vacuum,the residue was diluted with water, and extracted with EA (×2), driedover Na₂SO₄, filtered, concentrated, and purified by prep-HPLC with 5%to 95% ACN in 0.02% NH₄Ac on a C18, 4.6×50 mm column to give3-(4-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione (7.5 mg,4.3%) as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 7.69(d, J=4.4, 1H), 7.24 (d, J=4.8, 1H), 5.04-4.99 (m, 1H), 4.56-4.43 (m,2H), 2.90-2.86 (m, 1H), 2.62 (s, 1H), 2.38-2.34 (m, 1H), 2.03-1.99 (m,1H). MS (ESI) m/z=251 [M+H]⁺.

Compound 22:3-Cyclopentyl-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione

A solution of 4-bromo-3-methylthiophene-2-carboxylic acid (5.0 g, 18.25mmol) and aq. NaOH (3.75 N, 77.4 mL, 0.29 mol) was heated to 80° C. Thenpotassium permanganate (10.6 g, 66.5 mmol) was added in 4.21 g portionsto the warm solution over 2 h. The resultant suspension was heated toreflux temperature for 3 h then cooled to RT. The solid was filtered andwashed twice with 1 N NaOH and twice with water. The solution wasacidified to pH<3 with concentrated HCl, washed twice with DCM, andconcentrated to a solid residue. The crude product was recrystallizedfrom water to afford 4-bromothiophene-2,3-dicarboxylic acid (1.7 g, 30%)as a s white solid.

To a solution of 4-bromothiophene-2,3-dicarboxylic acid (1.7 g, 6.77mmol) in dry MeOH (10 mL) at 0° C. was added thionyl chloride (681 mg,5.72 mmol). Then the reaction was heated to 80° C. for 16 h. Thereaction was cooled to RT and the solvent was removed. The residue wasdiluted with water (20 mL) and extracted with EA (40 mL) twice. Thecombined organic layers were washed with sat. aq. NaHCO₃ (30 mL), brine,dried over Na₂SO₄, filtered, and concentrated and the residue purifiedon silica gel eluting with petroleum ether:EA (from 0% to 8%) to givedimethyl 4-bromothiophene-2,3-dicarboxylate (1.15 g, 61%) as a colorlessoil.

To a solution of dimethyl 4-bromothiophene-2,3-dicarboxylate (1.15 g,4.12 mmol) in toluene/water (40 mL/4 mL) was added2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.65 g,9.81 mmol), followed by K₂CO₃ (2.26 g, 16.35 mmol). The suspension waspurged with nitrogen twice. Then tetrakis(triphenylphosphine)palladium[Pd(PPh₃)₄] (957 mg, 1.31 mmol) was added and the mixture was heated at90° C. for 16 h. The reaction was cooled to RT and filtered. Thefiltrate was concentrated to give the crude product, which was purifiedon silica gel eluting with EA/petroleum ether (from 0% to 3%) to givedimethyl 4-(cyclopent-1-en-1-yl)thiophene-2,3-dicarboxylate (619 mg,56.6%) as a white solid.

To a solution of dimethyl4-(cyclopent-1-en-1-yl)thiophene-2,3-dicarboxylate (619 mg, 2.33 mmol)in THF (15 mL) at RT was added Pd/C (619 mg), the suspension was stirredat RT for 16 h under hydrogen (1 atm). The suspension was filtered andthe filtrate was concentrated to give dimethyl4-cyclopentylthiophene-2,3-dicarboxylate (573 mg, 92%) as a white solid.

To a solution of dimethyl 4-cyclopentylthiophene-2,3-dicarboxylate (573mg, 2.14 mmol) in MeOH (10 mL) at RT was added lithium hydroxide (154.1mg, 4.28 mmol), and the suspension was stirred at RT for 2 h. Thereaction was adjusted to pH=3 with 1 M HCl. The suspension wasconcentrated to give 4-cyclopentylthiophene-2,3-dicarboxylic acid (480mg, 94%) as a white solid.

The solution of 4-cyclopentylthiophene-2,3-dicarboxylic acid (100 mg,0.42 mmol) in acetic anhydride (5 mL) was heated to 140° C. for 2 h. Thesolvent was removed and the residue was dried in vacuo to give3-cyclopentylthieno[2,3-c]furan-4,6-dione (90 mg, crude) as an oil,which was used for the next step without purification.

The suspension of 3-cyclopentylthieno[2,3-c]furan-4,6-dione (90 mg, 0.41mmol) and 3-aminopiperidine-2,6-dione hydrochloride acid salt (333 mg,2.03 mmol) in THF (10 mL) was stirred at RT for 4 h. ThenN,N′-carbonyldiimidazole (CDI) (66 mg, 0.41 mmol) and4-dimethylaminopyridine (10 mg, 0.08 mmol) was added to the mixture,then the mixture was heated to 85° C. for 18 h. The mixture was purifiedon silica gel eluting with EA/petroleum ether from 20% to 60% to give3-cyclopentyl-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(17.0 mg, 12%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 7.36 (s, 1H), 5.05-5.00 (m, 1H), 3.44-3.40 (m, 1H), 2.88-2.82 (m,1H), 2.60-2.55 (m, 1H), 2.47-2.42 (m, 1H), 2.20-2.12 (m, 2H), 2.07-2.01(m, 1H), 1.77-1.60 (m, 6H). MS (ESI) m/z 332.8 [M+H]⁺.

Compound 23:3-(1-(Difluoromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

To a solution of methyl4-(bromomethyl)-5-(difluoromethyl)thiophene-3-carboxylate (420 mg, 1.47mmol) in DMF (10 mL) were added 3-aminopiperidine-2,6-dionehydrochloride acid salt (242 mg, 1.47 mmol) and TEA (447 mg, 4.42 mmol).The mixture was stirred at RT for 2 h. After the reaction was complete,the mixture was diluted with water and extracted with EA (30 mL×3). Thecombined organic layers were washed with brine, filtered, andconcentrated to afford residue, which was purified on silica gel elutingwith 10% MeOH in DCM to afford methyl5-(difluoromethyl)-4-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylate(300 mg, 61%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s,1H), 8.52 (s, 1H), 7.5 (t, J=54.4 Hz, 1H), 4.07-4.06 (m, 2H), 3.29-3.24(m, 1H), 2.95-2.82 (m, 1H), 2.53-2.52 (m, 1H), 2.14-2.07 (m, 1H),1.74-1.64 (m, 1H). MS (ESI) m/z 333.0 [M+H]⁺.

To a solution of5-(difluoromethyl)-4-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylate(200 mg, 0.6024 mmol) in ACN (10 mL) at 0° C. was addedtrimethylaluminium (4.8 mL, 1 M in toluene). The mixture was warmed toRT and continued stirring for 6 h. The reaction was quenched withammonium hydrochloride (aq.) and extracted with DCM (×2). The organiclayer was purified by prep-TLC to give3-(1-(difluoromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(5.6 mg, 3.1%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s,1H), 8.28 (s, 1H), 7.37 (t, J=55.6, 1H), 5.05-5.00 (m, 1H), 4.48-4.33(m, 2H), 2.92-2.83 (m, 1H), 2.64 (d, J=25.2, 1H), 2.37-2.33 (m, 1H),2.02-1.97 (m, 1H). MS (ESI) m/z=301 [M+H]⁺.

Compound 24:(S)-3-(3-Cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)azepane-2,7-dione

To a stirred solution of methyl 3-methylthiophene-2-carboxylate (10 g,0.064 mol) and NaOH (6.15 g, 0.15 mol) in AcOH glacial (38 mL) washeated to 60° C. Bromine (7.5 mL, 0.15 mol) was added dropwise andstirred at 85° C. for 12 h. The solution was allowed to cool to 50° C.and zinc (7.7 g, 0.12 mol) was added in portions, then the mixture wasstirred at 85° C. for 1 h. After 1 h, the reaction was cooled to RT andfiltered, then water and EA were added. The organic layer was washedwith water and concentrated to dryness to give methyl4-bromo-3-methylthiophene-2-carboxylate (12 g, 80%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.42 (s, 1H), 3.85 (s, 3H), 2.54 (s, 3H).

To a stirred solution of methyl 4-bromo-3-methylthiophene-2-carboxylate(0.5 g, 2.14 mmol) in carbon tetrachloride (8 mL) was addedN-bromosuccinimide (0.392 g, 2.2 mmol) and benzoyl peroxide (0.254 g,1.05 mmol). The mixture was stirred at 90° C. for 10 h. The mixture wasthen filtered, evaporated and purified on silica gel (petroleum) to givemethyl 4-bromo-3-(bromomethyl)thiophene-2-carboxylate (0.25 g, 37%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 7.47 (s, 1H), 4.89 (s, 2H), 3.92(s, 3H).

To a stirred solution of methyl4-bromo-3-(bromomethyl)thiophene-2-carboxylate (200 mg, 0.64 mmol) and(S)-3-aminoazepan-2-one (100 mg, 0.78 mmol) in DMF (4 mL) was added TEA(130 mg, 1.28 mmol). The mixture was stirred at RT for 2 h. After 2 h,water was added, and the crude mixture was extracted with EA. Theorganic layers were washed with brine, dried over Na₂SO₄, evaporated,and purified on silica gel (EA) to give (S)-methyl4-bromo-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate (160mg, 69%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.42 (s, 1H),5.88 (s, 1H), 4.15 (q, J=7.5 Hz, 2H), 3.89 (s, 3H), 3.32 (d, J=7.5 Hz,1H), 3.18-3.14 (m, 2H), 1.87-1.38 (m, 6H).

To a stirred solution of (S)-methyl4-bromo-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate (160mg, 0.44 mmol) in ACN (3 mL) was added trimethylaluminium (1 M solutionin hexane) (3 mL) slowly at 0° C. under nitrogen. The mixture wasstirred at RT overnight then quenched with saturated ammonium chlorideand extracted with EA. The organic layer was washed with water, brine,dried over Na₂SO₄, and evaporated to give(S)-3-bromo-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (150mg, 100%) as a yellow solid. MS (ESI) m/z=330.9 [M+H]⁺.

To a suspension of(S)-3-bromo-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (150mg, 0.46 mmol),2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (106 mg,0.55 mmol) and K₂CO₃ (190 mg, 1.38 mmol) in toluene (5 mL) and water(0.5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.04mmol). The mixture was stirred at 100° C. overnight under nitrogen.After cooling to RT, water was added and the mixture was extracted withEA. The organic layers were washed with brine, dried over Na₂SO₄,evaporated, and purified by prep-TLC (EA) to give(S)-3-(cyclopent-1-en-1-yl)-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(70 mg, 48%) as white solid. MS (ESI) m/z=317.0 [M+H]⁺.

To a stirred solution of(S)-3-(cyclopent-1-en-1-yl)-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(70 mg, 0.22 mmol) in THF (2 mL) was added 10% Pd/C (70 mg). The mixturewas stirred at RT overnight under hydrogen then filtered and evaporatedto give(S)-3-cyclopentyl-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(60 mg, 85%) as a white solid. MS (ESI) m/z=319.0 [M+H]⁺.

To a stirred solution(S)-3-cyclopentyl-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(60 mg, 0.19 mmol) in fluorobenzene (5 mL) and dimethyl sulfoxide (0.5mL) was added Dess-Martin reagent (200 mg, 0.47 mmol) at 0° C. Themixture was stirred at 80° C. overnight. After cooling to RT, thereaction was filtered. The filtrate was washed with aq. sodiumthiosulfate, aq. NaHCO₃, and brine, then dried over Na₂SO₄, evaporated,and purified by prep-TLC (petroleum/EA=1/1) to give(S)-3-(3-cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)azepane-2,7-dione(12 mg, 19%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s,1H), 7.64 (s, 1H), 5.13 (dd, J=5.6, 8.4 Hz, 1H), 4.46 (s, 2H), 3.10-3.02(m, 2H), 2.58-2.54 (m, 1H), 2.28-2.23 (m, 1H), 2.10-1.99 (m, 4H),1.80-1.72 (m, 3H), 1.65-1.53 (m, 4H). MS (ESI) m/z=333.1 [M+H]⁺.

Compound 25:(S)-3-(3-Chloro-1-methyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione

To a solution of(S)-3-(1-methyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione(50 mg, 0.179 mmol) in DMF (0.5 mL) at RT was added N-chlorosuccinimide(23 mg, 0.173 mmol). The mixture was stirred for 2 h followed by work upwith EA and sa.t aq. NaHCO₃ to give a solid after filtration andconcentration of the organic phase. Trituration with EA and hexanes gave(S)-3-(3-chloro-1-methyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione(35 mg, 63%) as a white solid. MS (ESI) m/z 313.8 [M+H]⁺. ¹H NMR(DMSO-d₆, 400 MHz) δ: 10.7 (s, 1H), 5.11 (d, 1H), 4.26 (d, 2H), 3.04 (m,1H), 2.56 (m, 1H), 2.17 (m, 1H), 2.02 (m, 2H), 1.81 (m, 1H).

Compound 26:2-Cyclopentyl-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione

A solution of 5-bromo-3-methylthiophene-2-carboxylic acid (5.0 g, 22.62mmol) and aq. NaOH (5.1 N, 100 mL, 0.51 mol) was heated to 80° C. thenpotassium permanganate (18.0 g, 113.9 mmol) was added in 3.0 g portionsto the warm solution over 1 h. The resultant suspension was heated toreflux temperature for 3 h then cooled to RT. The solid was filtered andwashed twice with 1 N NaOH and twice with water. The solution wasacidified to pH<3 with concentrated HCl, washed twice with water, andconcentrated to a solid residue. The crude product was recrystallizedfrom water to afford 5-bromothiophene-2,3-dicarboxylic acid (2.7 g, 47%)as a white solid.

To a solution of 5-bromothiophene-2,3-dicarboxylic acid (2.9 g, 11.55mmol) in dry MeOH (50 mL) at 0° C. was added thionyl chloride (2.74 g,23.10 mmol). Then the reaction was heated to 70° C. for 16 h. Thereaction was cooled to RT and the solvent was removed under vacuum. Theresidue was diluted with water (20 mL) and extracted with EA (40 mL)twice. The combined organic layers were washed with sat. aq. NaHCO₃ (30mL) and brine, then dried over Na₂SO₄, filtered, and concentrated togive crude product, which was purified on silica gel eluting withpetroleum ether: EA (from 0% to 8%) to give dimethyl5-bromothiophene-2,3-dicarboxylate (2.0 g, 62%) as a colorless oil.

To a solution of dimethyl 5-bromothiophene-2,3-dicarboxylate (500 mg,1.79 mmol) in dioxane/water (10 mL/1 mL) was added2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (695 mg,3.58 mmol), followed by cesium carbonate (1.46 g, 4.48 mmol) was added.The suspension was purged with nitrogen for twice. Thentetrakis(triphenylphosphine)palladium [Pd(PPh₃)₄] (414 mg, 0.36 mmol)was added and the mixture was heated at 90° C. for 16 h. The reactionwas cooled to RT and filtered. The filtrate was concentrated to give thecrude product, which was purified on silica gel eluting withEA/petroleum ether (from 0% to 5%) to give dimethyl5-(cyclopent-1-en-1-yl)thiophene-2,3-dicarboxylate (410 mg, 86%) as awhite solid.

To a solution of dimethyl5-(cyclopent-1-en-1-yl)thiophene-2,3-dicarboxylate (410 mg, 1.54 mmol)in THF (10 mL) at RT was added Pd/C (200 mg), the suspension was stirredat RT for 6 h under hydrogen (1 atm). The suspension was filtered, thefiltrate was concatenated to give dimethyl5-cyclopentylthiophene-2,3-dicarboxylate (390 mg, 94%) as a white solid.

To a solution of dimethyl 5-cyclopentylthiophene-2,3-dicarboxylate (390mg, 1.45 mmol) in MeOH (10 mL) at RT was added lithium hydroxide (305mg, 7.27 mmol), the suspension was stirred at RT for 2 h. The reactionwas adjusted to pH=3 with 1 M HCl. The suspension was concentrated togive 5-cyclopentylthiophene-2,3-dicarboxylic acid (330 mg, 94%) as awhite solid.

To a solution of 5-cyclopentylthiophene-2,3-dicarboxylic acid (280 mg,1.17 mmol) in acetic anhydride (7 mL). The reaction was heated to 140°C. for 2 h. The solvent was removed and the residue was dried in vacuoto give 2-cyclopentylthieno[2,3-c]furan-4,6-dione (300 mg, crude) as awhite oil, which was used for the next step without purification.

The suspension of 2-cyclopentylthieno[2,3-c]furan-4,6-dione (300 mg,1.35 mmol) and 3-aminopiperidine-2,6-dione hydrochloride acid salt (1.02g, 6.75 mmol) in THF (8 mL) was stirred at RT for 4 h. ThenN,N′-carbonyldiimidazole (CDI) (215 mg, 1.35 mmol) and4-dimethylaminopyridine (32 mg, 0.27 mmol) was added to the mixture,then heated to 85° C. for 18 h. The mixture was purified on silica geleluting with EA/petroleum ether from 20% to 60% to give2-cyclopentyl-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(180 mg, 46%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 7.36 (s, 1H), 5.05-5.00 (m, 1H), 3.44-3.40 (m, 1H), 2.91-2.82 (m,1H), 2.60-2.55 (m, 1H), 2.50-2.42 (m, 1H), 2.18-2.12 (m, 2H), 2.07-2.02(m, 1H), 1.80-1.61 (m, 6H). MS (ESI) m/z 331.1 [M−H]⁺.

Compound 27:1-Cyclopentyl-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione

To a solution of methyl 2-oxopropanoate (20 g, 176.3 mmol) in DMF (200mL) was added ethyl 2-cyanoacetate (20 g, 195.9 mmol) and sulfur (7.54g, 235.1 mmol). The mixture was stirred at RT, then TEA (46 mL, 331.8mmol) was added slowly over 10 min. The reaction was heated to 50° C.and stirred overnight. The reaction was cooled to RT and poured intowater (300 mL) and brine (30 mL) mixture, extracted with EA (3×200 mL).The organic phase was washed with water (2×200 mL), followed by brine(200 mL), then dried over Na₂SO₄, filtered and concentrated to affordcrude product, which was purified on silica gel to afford 3-ethyl4-methyl 2-aminothiophene-3,4-dicarboxylate (24.79 g, 61.34%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.26 (s, 2H), 6.70 (s, 1H),4.10 (m, 2H), 3.68 (s, 3H), 1.17 (m, 3H). MS (ESI) m/z 230.1 [M+H]⁺.

3-Ethyl 4-methyl 2-aminothiophene-3,4-dicarboxylate (24.79 g, 108.1mmol) in HCl (500 mL, 2N) was cooled to 0° C. and sodium nitrite (11.2g, 162.2 mmol) was added. The mixture was stirred at 0° C. for 30 min.Then potassium iodide (44.83 g, 270.4 mmol) was added in small portions.The mixture was warmed up to RT and stirred for 45 min. The mixture waspoured into water (250 mL) and extracted with EA (3×200 mL). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedto afford crude product, which was purified on silica gel to afford3-ethyl 4-methyl 2-iodothiophene-3,4-dicarboxylate (18.19 g, 49.46%) asa yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H), 4.30-4.32 (m,2H), 4.10-4.15 (m, 2H), 3.77 (s, 3H), 1.26-12.9 (m, 3H). MS (ESI) m/z341.0 [M+H]⁺.

To a solution of 3-ethyl 4-methyl 2-iodothiophene-3,4-dicarboxylate (3.0g, 8.82 mmol),2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.48 g,8.82 mmol) and K₂CO₃ (3.04 g, 22.05 mmol) in toluene/water (50 mL/5 mL)was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)[Pd(dppf)₂Cl₂] (1.29 g, 1.76 mmol) under nitrogen. The suspension washeated to reflux and stirred for 16 h. Then the mixture was poured intowater (100 mL) and extracted with EA (3×50 mL). The combined organicphase was dried over Na₂SO₄, filtered and concentrated to afford crudeproduct, which was purified on silica gel to afford 3-ethyl 4-methyl2-(cyclopent-1-en-1-yl)thiophene-3,4-dicarboxylate (1.395 g, 56.43%). aswhite solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (s, 1H), 6.10 (s, 1H),4.24-4.27 (m, 2H), 3.75 (s, 3H), 2.57-2.62 (m, 2H), 2.422.46 (m, 2H),1.91-1.95 (m, 2H), 1.21-1.25 (m, 3H). MS (ESI) m/z 281.0 [M+H]⁺.

To a solution of 3-ethyl 4-methyl2-(cyclopent-1-en-1-yl)thiophene-3,4-dicarboxylate (1.342 g, 4.79 mmol)in MeOH (25 mL) was added Pt—C(10% of content, 0.3 g). The suspensionwas degassed under vacuum and purged with hydrogen twice. The mixturewas stirred under hydrogen atmosphere for 2 h. The suspension wasfiltered and the filtrate was concentrated to give 3-ethyl 4-methyl2-cyclopentylthiophene-3,4-dicarboxylate (1.304 g, 96.48%) as acolorless oil. ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (s, 1H), 4.23-4.25 (m,2H), 3.75 (s, 3H), 2.40 (s, 1H), 2.06-2.12 (m, 2H), 1.651.70 (m, 6H),1.251.28 (m, 3H). MS (ESI) m/z 283.1 [M+H]⁺.

A solution of 3-ethyl 4-methyl 2-cyclopentylthiophene-3,4-dicarboxylate(1.303 g, 4.615 mmol) in HCl (25 mL, 2N) was refluxed and stirred for 16h. Then the mixture was cooled to RT and the solvent was removed undervacuum. The crude product was purified on silica gel to afford2-cyclopentylthiophene-3,4-dicarboxylic acid (0.962 g, 86.7%) as yellowsolid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.05 (br, 2H), 7.92 (s, 1H), 3.15(s, 1H), 1.98-2.01 (m, 2H), 1.73-1.75 (m, 6H). MS (ESI) m/z 240.1[M+H]⁺.

To a solution of 2-cyclopentylthiophene-3,4-dicarboxylic acid (120 mg,0.5 mmol) in acetic anhydride (10 mL) at RT. The mixture was refluxed at135° C. overnight. The solvent was removed to give the crude4-cyclopentylthieno[3,4-c]furan-1,3-dione (100 mg, crude) as a yellowoil, which was used directly for next step.

To a solution of 4-cyclopentylthieno[3,4-c]furan-1,3-dione (50 mg, 0.22mmol) in THF (4 mL) was added 3-aminopiperidine-2,6-dione hydrochlorideacid salt (181.5 mg, 1.1 mmol), N,N′-carbonyldiimidazole (35.6 mg, 0.22mmol) and 4-dimethylaminopyridine (5.4 mg, 0.44 mmol). The suspensionwas heated at 70° C. overnight. After the reaction was completed, thesolvent was removed to give the crude product, which was purified byprep-TLC with petroleum ether in EA from 10% to 20% to give1-cyclopentyl-5-(2,6-dioxopiperidin-3-yl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(20 mg, 27.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (d,J=6.4 Hz, 1H), 8.19 (s, 1H), 5.05-5.00 (m, 1H), 3.62-3.35 (m, 1H),2.91-2.82 (m, 1H), 2.59-2.50 (m, 1H), 2.46-2.42 (m, 1H), 2.19-2.18 (m,2H), 2.05-1.97 (m, 1H), 1.81 (s, 2H), 1.67 (s, 4H). MS (ESI) m/z 333.1[M+H]⁺.

Compound 28:(S)-1-Methyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one

To a solution of(S)-1-bromo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(300 mg, 0.9146 mmol) in dioxane/water (12 mL/4 mL) at RT was addedcesium carbonate (891.8 mg, 2.744 mmol). The atmosphere was exchangedwith nitrogen twice. Then 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane(1.2 mL) and tetrakis(triphenylphosphine)palladium [Pd(PPh₃)₄] (105.7mg, 0.09146 mmol) were added. The resulting suspension was stirred at90° C. overnight. The mixture was cooled to RT and concentrated undervacuum. The resulting residue was diluted with water and extracted withDCM (×2). The combined organic layer was dried over Na₂SO₄, filtered,and concentrated to give the crude product, which was purified on silicagel eluting with petroleum ether/EA from 0% to 6% to give(S)-1-methyl-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one(59.4 mg, 24.6%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.81(t, J=5.2 Hz, 1H), 7.71 (s, 1H), 4.81 (d, J=10.4 Hz, 1H), 4.36 (dd,J=14.8 Hz, 2H), 3.27-3.19 (m, 1H), 3.12-3.07 (m, 1H), 2.41 (s, 3H), 1.98(t, J=10.0 Hz, 2H), 1.84-1.66 (m, 3H), 1.32-1.24 (m, 1H). MS (ESI) m/z265 [M+H]⁺.

Compound 29:3-(4-Oxo-1-(trifluoromethyl)-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

To a stirred solution of3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(230 mg, 0.7 mmol) in DMF (5 mL) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (400 mg, 2.1 mmol), cuprousiodide (110 mg, 0.58 mmol) and 2 drops of hexamethylphosphoramide undernitrogen. The mixture was stirred at 80° C. for 2 days. Then the mixturewas diluted with water and extracted with EA. The organic layer waswashed with sat. aq. NaHCO₃ and brine, dried over Na₂SO₄, evaporated andpurified by prep-HPLC with 5% to 95% ACN in 0.02% NH₄Ac on a C18, 4.6×50mm column to give (20 mg, 9%) as a yellow solid. MS (ESI) m/z 318.8[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.47 (s, 1H), 5.04(dd, J=5.2, 13.6 Hz, 1H), 4.45 (q, J=16.8 Hz, 2H), 2.89-2.85 (m, 1H),2.60-2.56 (m, 1H), 2.41-2.36 (m, 1H), 2.00-1.97 (m, 1H).

Compound 30:(S)-1-(3-Chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of (S)-tert-butyl((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(60 mg, 0.1526 mmol) in DCM (4 mL) at 0° C. was added2,2,2-trifluoroacetic acid (1 mL). The mixture was warmed to RT andstirred for 1.5 h. It was concentrated to remove the solvent and theresidue was diluted in water and washed with DCM. The aqueous layer wasdried in vacuo to give(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoroacetic acid salt (44.7 mg, 100%) as a white solid. MS(ESI) m/z 294 [M+H]⁺.

To a solution of(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoroacetic acid salt (44.7 mg, 0.1526 mmol) in THF (3 mL) at0° C. was added 2-chloro-4-isocyanato-1-methylbenzene (30.7 mg, 0.1832mmol) and TEA (38.6 mg, 0.3815 mmol). The mixture was warmed to RT andstirred for 2 h. It was concentrated and purified on silica gel elutingwith DCM/MeOH from 0% to 10% to give(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(29.4 mg, 41.9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s,1H), 8.78 (s, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.21-7.14 (m, 2H), 6.85(t, J=6.0, 1H), 5.15 (dd, J=4.8, 12.0, 1H), 4.42 (dd, J=4.8, 17.6, 4H),3.10-3.03 (m, 1H), 2.57 (d, J=17.2, 1H), 2.24 (s, 3H), 2.18-2.15 (m,1H), 2.10-2.00 (m, 2H), 1.84-1.79 (m, 1H). MS (ESI) m/z 461 [M+H]⁺.

Compound 31:(S)-2-(3-Chloro-4-methylphenyl)-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide

To a solution of 2-(3-chloro-4-methylphenyl)acetic acid (70 mg, 0.38mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole (HOBt) (78 mg, 0.57mmol) and3-(ethyliminomethylideneamino)—N,N-dimethylpropan-1-amine,hydrochloride(EDCI) (109 mg, 0.57 mmol), followed by diethylisopropylamine (98 mg,0.76 mmol). Then to the reaction was added(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoroacetic acid salt. The resulting solution was stirred atRT for 16 h. The reaction was diluted with water (10 mL), extracted withEA (20 mL×2). The combined organic layers were concentrated to give thecrude product, which was purified by prep-HPLC with 5% to 95% ACN in0.02% NH₄Ac on a C18, 4.6×50 mm column to give(S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(39 mg, 22.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.67 (s,1H), 8.71 (t, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.33 (s, 1H), 7.26 (d, J=7.6Hz, 1H), 7.13 (d, J=6.4 Hz, 1H), 5.11 (dd, J=6.4, 12.0 Hz, 1H), 4.42 (d,J=5.6 Hz, 2H), 4.23 (q, J=13.6 Hz, 2H), 3.44 (s, 2H), 3.08-3.00 (m, 1H),2.56 (d, J=15.6 Hz, 1H), 2.28 (s, 3H), 2.08-1.94 (m, 3H), 1.82-1.75 (m,1H). MS (ESI) m/z=460.0, 462.0 [M+H]⁺.

Compound 32:(S)-1-(3-Chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) wasadded dropwise a solution of 3-chloro-4-(trifluoromethyl)aniline (100mg, 0.51 mmol) and refluxed at 80° C. for 0.5 h. Then the mixture wasconcentrated to give 2-chloro-4-isocyanato-1-(trifluoromethyl)benzene.To the solution of 2-chloro-4-isocyanato-1-(trifluoromethyl)benzene inTHF was added(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (52.2 mg, 0.18 mmol), followedby TEA (34 mg, 0.34 mmol). The mixture was stirred at RT for 2 h. Themixture was concentrated to give crude product, which was purified byprep-HPLC with 5% to 95% ACN in 0.02% NH₄Ac on a C18, 4.6×50 mm columnto give(S)-1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(6.5 mg, 7.1%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s,1H), 9.34 (s, 1H), 7.88 (s, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 7.11 (t, J=6.0 Hz, 1H), 5.14 (dd, J=7.6, 12.4 Hz, 1H), 4.46 (d,J=5.2 Hz, 2H), 4.40 (d, J=4.8 Hz, 2H), 3.07-3.01 (m, 1H), 2.57-2.49 (m,1H), 2.19-1.96 (m, 3H), 1.88-1.76 (m, 1H). MS (ESI) m/z 515.0, 517.0[M+H]⁺

Compound 33:1-(3-Chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroacetic acid salt (61.8 mg, 0.2216 mmol) in THF (3 mL) at0° C. was added TEA (56.1 mg, 0.554 mmol) and2-chloro-4-(isocyanatomethyl)-1-methylbenzene (80.5 mg, 0.4432 mmol).The mixture was warmed to RT for 4 h. The compound was consumedcompletely and a new spot was present. The mixture was concentrated toafford residue, which was purified on silica gel eluting with MeOH inDCM from 0% to 10% to give1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(31.8 mg, 31.2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s,1H), 7.84 (s, 1H), 7.27-7.10 (m, 3H), 6.64 (d, J=17.6, 2H), 5.00 (d,J=13.2, 1H), 4.36-4.14 (m, 6H), 2.92-2.85 (m, 1H), 2.57 (d, J=18.4, 1H),2.28 (s, 3H), 2.22-2.19 (m, 1H), 1.97-1.94 (m, 1H). MS (ESI) m/z=461[M+H]⁺.

Compound 34:(S)-1-(3-Chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To the solution of(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (101.5 mg, 0.26 mmol) in THF (4mL) was added 2-chloro-4-(isocyanatomethyl)-1-methylbenzene (56 mg, 0.31mmol), followed by TEA (52 mg, 0.52 mmol). The mixture was stirred at RTfor 2 h. The reaction was concentrated to give the crude product, whichwas purified by prep-HPLC with 5% to 95% ACN in 0.02% NH₄Ac on a C18,4.6×50 mm column to give(S)-1-(3-chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(43.3 mg, 45.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s,1H), 7.85 (s, 1H), 7.27-7.25 (m, 2H), 7.11 (dd, J=6.0, 7.6 Hz, 1H),6.69-6.61 (m, 2H), 5.13 (dd, J=6.4, 12.0 Hz, 1H), 4.38-4.27 (m, 4H),4.19 (d, J=6.0 Hz, 2H), 3.09-3.02 (m, 1H), 2.56 (d, J=18.0 Hz, 1H), 2.28(s, 3H), 2.09-1.96 (m, 3H), 1.79-1.76 (m, 1H). MS (ESI) m/z=475.1,477.1[M+H]⁺.

Compound 35:(S)-1-(3-Chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a solution of methyl 5-bromo-3-methylthiophene-2-carboxylate (2.3 g,9.79 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide(NBS) (1.83 g, 10.3 mmol) and benzoyl peroxide (BPO) (240 mg, 0.98mmol), the suspension was heated at 80° C. for 16 h. The reaction wascooled to RT and filtered the solid. The filtrate was concentrated togive the crude product, which was purified on silica gel eluting withpetroleum ether/EA from 0% to 5% to give methyl5-bromo-3-(bromomethyl)thiophene-2-carboxylate (2.7 g, crude) as a whitesolid.

To a solution of methyl 5-bromo-3-(bromomethyl)thiophene-2-carboxylate(2.7 g, 8.6 mmol) in DMF (25 mL) was added (S)-3-aminoazepan-2-one (1.1g, 8.6 mmol), followed by TEA (1.74 g, 17.2 mmol). The suspension wasstirred at RT for 1 h. The solvent was removed and purified on silicagel eluting with petroleum ether/EA from 50% to 100% to give (S)-methyl5-bromo-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate (1.42g, 45%) as a white solid. MS (ESI) m/z 360.9 [M+H]⁺.

To a solution of (S)-methyl5-bromo-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate (1.67g, 4.63 mmol) in ACN (50 mL) at 0° C. was added Trimethylaluminium (37mL, 37 mmol, IM in toluene). The suspension was stirred at RT for 4 h.The mixture was quenched with NH₄Cl at 0° C., then the mixture wasextracted with DCM (80 mL×2), washed with brine (70 mL), dried overNa₂SO₄, and concentrated in vacuo to get the crude product, which waspurified on silica gel eluting with petroleum ether/EA from 50% to 100%to give(S)-2-bromo-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (1.0g, 65%) as a white solid. MS (ESI) m/z 328.9 [M+H]⁺

To a solution of(S)-2-bromo-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (1.2g, 3.68 mmol) in DMF was added tris(dibenzylideneacetone)dipalladium(0)[Pd₂(dba)₃] (205 mg, 0.22 mmol), 1,1′-bisdiphenylphosphinoferrocene[dppf] (233 mg, 0.43 mmol) and zinc cyanide (278 mg, 2.38 mmol). Themixture was stirred at 150° C. for 1 h in a microwave under nitrogenatmosphere. The mixture was concentrated to give crude product, whichwas purified on silica gel eluting with petroleum ether/EA from 50% to100% to give(S)-6-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonitrile(460 mg, 46%) as a red solid. MS (ESI) m/z 276.0 [M+H]⁺.

To a solution of(S)-6-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonitrile(360 mg, 1.31 mmol) in ACN/DMSO (21 mL/3.5 mL, 1 drop water in DMSO) wasadded Dess-Martin periodinane (1.38 g, 3.27 mmol). The suspension washeated at 80° C. for 16 h. The mixture was cooled to RT and 20 mL of asaturated sodium thiosulfate solution was added followed by stirring for5 min. The mixture was extracted with DCM (30 mL×2) and the combinedsolution was washed with 10% aq. sodium thiosulfate/aq. NaHCO₃ (1:1mixture) (50 mL) and brine (50 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated to afford the crude product, whichwas purified on silica gel eluting with petroleum ether/EA from 50% to100% to give(S)-5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonitrile(300 mg, 62%) as a white solid. MS (ESI) m/z 289.9 [M+H]⁺.

To a solution of(S)-5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonitrile(250 mg, 0.86 mmol) in THF (15 mL) was added Raney Ni (200 mg), followedby Di-tert-butyl dicarbonate [(Boc)₂O] (377 g, 1.73 mmol). Thesuspension was stirred at RT under hydrogen for 16 h. The suspension wasfiltered and the filter cake was washed with DCM (10 mL). The combinedfiltrate was concentrated to give the crude product, which was purifiedon silica gel eluting with DCM/MeOH from 0% to 4% to give (S)-tert-butyl((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate (180 mg, 44%) as a white solid. MS (ESI) m/z 392.0 [M−H]⁺.

To a solution of (S)-tert-butyl((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)carbamate (80.0 mg, 0.20 mmol) in DCM (4 mL) was added2,2,2-trifluoactic acid (1.5 mL) at 0° C., and the solution was stirredat RT for 2 h. The suspension was concentrated to give crude product(60.0 mg), which was used directly for next step without furtherpurification.

To a solution of(S)-3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)azepane-2,7-dione(60.0 mg, 0.20 mmol) dissolved in DMF (4 mL) was added TEA (42 mg, 0.41mmol) and the suspension was stirred at RT, then2-chloro-4-isocyanato-1-methylbenzene (69.0 mg, 0.41 mmol) was added tothe mixture and stirred at RT for 2 h. The mixture was purified onsilica gel eluting with DCM/MeOH from 0% to 10% to give(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea(53.0 mg, 56%) a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H),8.77 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.20-7.13 (m, 2H), 6.89-6.86 (m,1H), 5.14-5.10 (m, 1H), 5.20 (d, J=6 Hz, 2H), 4.51 (d, J=2.4 Hz, 2H),3.08-3.04 (m, 1H), 2.59-2.53 (m, 1H), 2.25-2.16 (m, 4H), 2.10-1.98 (m,2H), 1.81-1.75 (m, 1H). MS (ESI) m/z 461.1 [M+H]⁺.

Compound 36:(S)-1-(5-Chloro-2,4-dimethylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of 5-chloro-2,4-dimethylaniline (27.5 mg, 0.18 mmol) inDCM (4 mL) was added 4-nitrophenyl chloroformate (35.7 mg, 0.18 mmol) atRT and stirred for 1 h. Then(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluroacetic acid salt (51.9 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The resulting solution was stirred at RT for2 h. The reaction was concentrated to give the crude product, which waspurified by prep-HPLC to give(S)-1-(5-chloro-2,4-dimethylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(26.1 mg, 31.1%) as a white solid. MS (ESI) m/z 474.8 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 7.87 (d, J=6.4 Hz, 3H), 7.18 (t,J=5.6 Hz, 1H), 7.10 (s, 1H), 5.14 (dd, J=7.2, 12.0 Hz, 1H), 4.46 (d,J=4.8 Hz, 2H), 4.39 (d, J=4.0 Hz, 2H), 3.09-3.01 (m, 1H), 2.56 (d,J=16.4 Hz, 1H), 2.22 (s, 3H), 2.16-1.96 (m, 6H), 1.84-1.77 (m, 1H).

Compound 37:(S)-1-((5-(2,7-Dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(6-methylpyridin-3-yl)urea

To a solution of 6-methylpyridin-3-amine (27.4 mg, 0.25 mmol) in DCM (4mL) was added 4-nitrophenyl chloroformate (50.3 mg, 0.25 mmol) at RT andstirred for 1 h. Then(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (74.5 mg, 0.25 mmol) was added,followed by TEA (36 mg, 0.36 mmol). The mixture was stirred at RT for 2h. The mixture was concentrated to give the crude product, which waspurified by prep-HPLC to give(S)-1-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(6-methylpyridin-3-yl)urea(13.2 mg, 12.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s,1H), 8.74 (s, 1H), 8.41 (d, J=2.8 Hz, 1H), 7.87 (s, 1H), 7.75 (dd,J=5.6, 8.4 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.88 (t, J=6.0 Hz, 1H), 5.14(dd, J=6.8, 12.0 Hz, 1H), 4.44 (d, J=4.4 Hz, 2H), 4.39 (d, J=5.2 Hz,2H), 3.08-3.01 (m, 1H), 2.54 (d, J=21.2 Hz, 1H), 2.37 (s, 3H), 2.17-1.96(m, 3H), 1.82-1.77 (m, 1H). MS (ESI) m/z 427.8[M+H]⁺.

Compound 38:(S)-1-((5-(2,7-Dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea

To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) wasadded dropwise a solution of 4-methyl-3-(trifluoromethyl)aniline (100mg, 0.51 mmol) and refluxed at 80° C. for 0.5 h. Then the mixture wasconcentrated to give crude4-isocyanato-1-methyl-2-(trifluoromethyl)benzene. To the solution ofcrude 4-isocyanato-1-methyl-2-(trifluoromethyl)benzene in THF (4 ml) wasadded(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (52.2 mg, 0.18 mmol), followedby TEA (34 mg, 0.34 mmol). The mixture was stirred at RT for 2 h. Themixture was concentrated to give crude product, which was purified byprep-HPLC to give(S)-1-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea(25.7 mg, 29.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s,1H), 8.94 (s, 1H), 7.89 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.48 (dd,J=6.4, 8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.89 (t, J=6.0 Hz, 1H), 5.14(dd, J=6.8, 12.0 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 4.39 (d, J=4.8 Hz,2H), 3.09-3.01 (m, 1H), 2.57-2.55 (m, 1H), 2.34 (s, 3H), 2.16-1.95 (m,3H), 1.82-1.76 (m, 1H). MS (ESI) m/z 495.1 [M+H]⁺.

Compound 39:(S)-1-(3-Chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a solution of(S)-3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)azepane-2,7-dione(75.0 mg, 0.25 mmol) dissolved in DMF (5 mL) was added TEA (52.0 mg,0.51 mmol) and the suspension was stirred at RT, then2-chloro-4-(isocyanatomethyl)-1-methylbenzene (93.0 mg, 0.51 mmol) wasadded to the mixture and stirred at RT for 2 h. The mixture was purifiedon silica gel eluting with DCM/MeOH from 0% to 10% to give(S)-1-(3-chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea(22.9.0 mg, 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s,1H), 7.28-7.07 (m, 4H), 6.77-6.63 (m, 2H), 5.14-5.10 (m, 1H), 4.46-4.35(m, 4H), 4.19 (d, J=5.6 Hz, 2H), 3.08-3.01 (m, 1H), 2.58-2.50 (m, 1H),2.28-2.17 (m, 4H), 2.12-1.99 (m, 2H), 1.82-1.77 (m, 1H). MS (ESI) m/z475.1 [M+H]⁺.

Compound 40:1-(3-Chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a solution of 5-bromo-3-methylthiophene-2-carboxylic acid (5 g, 22.6mmol) in a mixture of DCM (80 mL) and DMF (1 mL) was added oxalylchloride (5.7 g, 45.2 mmol) dropwise at 0° C. The mixture was stirred atRT for 4 h. Then the solvent was removed under vacuum and residue wasdissolved with DCM (50 mL). Potassium tert-butoxide (7.6 g, 67.8 mmol)was added portion wise to the solution at 0° C., and the mixture wasstirred at RT for 30 min. Solvent was removed under vacuum and residuewas purified on silica gel eluting with petroleum ether to givetert-butyl 5-bromo-3-methylthiophene-2-carboxylate as a pale yellow oil(3 g, 48%).

To a solution of tert-butyl 5-bromo-3-methylthiophene-2-carboxylate (3.0g, 10.8 mmol) in carbon tetrachloride (30 mL) were addedN-bromosuccinimide (NBS) (1.92 g, 10.8 mmol) and Benzoyl peroxide (0.52g, 2.16 mmol). The mixture was stirred at 80° C. overnight. After thereaction was completion, the solvent was removed and residue waspurified on silica gel eluting with petroleum ether to give tert-butyl5-bromo-3-(bromomethyl)thiophene-2-carboxylate as a colorless oil (2.6g, 67%).

To a solution of tert-butyl5-bromo-3-(bromomethyl)thiophene-2-carboxylate (2.4 g, 6.72 mmol) in DMF(30 mL) was added 3-aminopiperidine-2,6-dione (1.1 g, 6.72 mmol) and TEA(1.36 g, 13.44 mmol). The mixture was stirred at 80° C. overnight. Afterconcentration under vacuum, the residue was diluted with water (20 mL)and extracted with EA. The organic layers were combined, dried overNa₂SO₄ and concentrated to give the crude product, which was purified onsilica gel eluting with EA/petroleum ether (0% to 45%) to givetert-butyl5-bromo-3-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-2-carboxylateas a green solid. (500 mg, 18.5%). MS (ESI) m/z 402.9 [M+1⁺].

To a solution of tert-butyl5-bromo-3-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-2-carboxylate(500 mg, 1.24 mmol) in DCM (20 mL) was added 2,2,2-trifluoroacetic acid(5 mL). The mixture was stirred at RT overnight. Then the solvent wasremoved to afford5-bromo-3-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-2-carboxylicacid (440 mg, 100%), which was directly used in the next step withoutfurther purification. MS (ESI) m/z 346.8 [M+1]⁺.

To a solution of5-bromo-3-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-2-carboxylicacid (430 mg, 1.24 mmol) in DMF (30 mL) was added2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (590 mg, 1.55 mmol) and DIEA (400 mg, 3.1mmol). The mixture was stirred at RT for 3 h. After the reaction wascompletion, the solvent was removed under vacuum to afford residue,which was diluted with water (10 mL), extracted with DCM. The organiclayers were dried over Na₂SO₄, concentrated and triturated with EA togive3-(2-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(360 mg, 88%) as white solid. MS (ESI) m/z 328.9 [M+1]⁺.

To a solution of3-(2-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(310 mg, 0.95 mmol) in DMF (5 mL) was addedtris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] (90 mg, 0.095mmol), 1,1′-bisdiphenylphosphinoferrocene [dppf] (128 mg, 0.23 mmol) andZinc cyanide (122 mg, 1.04 mmol). The mixture was stirred at 150° C.under microwave for 1 h. After the reaction was completion, the solventwas removed to afford residue, which was purified on silica gel elutingwith EA/petroleum ether (20% to 100%) to give5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonitrile(138 mg, 53%) as a pale brown solid. MS (ESI) m/z 276.0 [M+1]⁺.

To a suspension of5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonitrile(50 mg, 0.18 mmol) and Raney nickel (50 mg) in THF (5 mL) was added2-chloro-4-isocyanato-1-methylbenzene (66 mg, 0.36 mmol). The mixturewas purged with hydrogen and stirred at RT for 7 h. After the reactionwas completion, Raney nickel was filtered, the resulting solution wasconcentrated and purified by prep-HPLC to give1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea(9.9 mg, 12.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 8.80 (s, 1H), 7.65 (s, 1H), 7.19-6.89 (m, 3H) 6.89-6.88 (app.t, J=6Hz, 1H), 4.98-4.95 (dd, J=4.4, 13.2 Hz, 1H), 4.52-4.51 (d, J=4.4 Hz,2H), 4.36-4.18 (q, J=13.2 Hz, 2H), 2.81-2.83 (m, 1H), 2.59-2.55 (m, 1H),2.35-2.31 (m, 1H), 2.23 (s, 3H), 1.99-1.98 (m, 1H). MS (ESI) m/z 447.0[M+1]⁺.

Compound 41:(S)-1-(3-Chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiourea

To the solution of(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (70.3 mg, 0.18 mmol) in THF (4mL) was added 2-chloro-4-(isothiocyanatomethyl)-1-methylbenzene (33 mg,0.18 mmol), followed by TEA (36 mg, 0.36 mmol). The mixture was stirredat RT for 2 h. The reaction was concentrated to give the crude product,which was purified by prep-HPLC to give(S)-1-(3-chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiourea(43.3 mg, 45.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s,1H), 9.75 (s, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.30 (d, J=8.0 Hz, 1H),7.18 (dd, J=6.4, 8.4 Hz, 1H), 5.15 (dd, J=7.2, 11.6 Hz, 1H), 4.88 (d,J=6.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 3.09-3.02 (m, 1H), 2.56 (d,J=18.0 Hz, 1H), 2.29 (s, 3H), 2.17-1.99 (m, 3H), 1.84-1.79 (m, 1H). MS(ESI) m/z=477.0, 479.0[M+H]⁺.

Compound 42:(S)-1-((5-(2,7-Dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-isopropyl-4-methylphenyl)urea

To a solution of 3-isopropyl-4-methylaniline (26.5 mg, 0.18 mmol) in DCM(4 mL) was added 4-nitrophenyl chloroformate (35.8 mg, 0.18 mmol) at RTand stirred for 1 h. Then(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoroacetic acid salt (52.2 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The mixture was stirred at RT for 2 h. Thereaction was concentrated to give the crude product, which was purifiedby prep-HPLC to give(S)-1-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-isopropyl-4-methylphenyl)urea(25.1 mg, 30.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s,1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.14 (dd,J=6.0, 8.4 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.67 (t, J=6.8 Hz, 1H), 5.14(dd, J=6.8, 11.6 Hz, 1H), 4.43 (d, J=5.6 Hz, 2H), 4.39 (d, J=4.4 Hz,2H), 3.05-3.01 (m, 2H), 2.56 (d, J=16.8 Hz, 1H), 2.20 (s, 3H), 2.17-1.96(m, 3H), 1.82-1.77 (m, 1H), 1.13 (d, J=6.8 Hz, 6H). MS (ESI)m/z=469.2[M+H]⁺.

Compound 43:(S)-1-(3-Chloro-5-isopropyl-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of 3-chloro-5-isopropyl-4-methylaniline (32.6 mg, 0.18mmol) in DCM (4 mL) was added 4-nitrophenyl chloroformate (35.8 mg, 0.18mmol) at RT and stirred for 1 h. Then(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoroacetic acid salt (52.2 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The mixture was stirred at RT for 2 h. Thereaction was concentrated to give the crude product, which was purifiedby prep-HPLC to give(S)-1-(3-chloro-5-isopropyl-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(23.8 mg, 26.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s,1H), 8.76 (s, 1H), 7.87 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.09 (d, J=1.6Hz, 1H), 6.80 (t, J=5.6 Hz, 1H), 5.14 (dd, J=4.0, 11.6 Hz, 1H), 4.43 (d,J=4.8 Hz, 2H), 4.39 (d, J=4.8 Hz, 2H), 3.14-3.01 (m, 2H), 2.59-2.56 (m,1H), 2.24 (s, 3H), 2.16-1.97 (m, 3H), 1.82-1.76 (m, 1H), 1.14 (d, J=11.2Hz, 6H). MS (ESI) m/z 503.1, 505.1[M+H]⁺.

Compound 44:1-(3-Chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

To a suspension of5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carbonitrile(40 mg, 0.14 mmol) and Raney nickel (50 mg) in THF (3 mL) was added2-chloro-4-(isocyanatomethyl)-1-methylbenzene (136 mg, 0.7 mmol). Themixture was purged with hydrogen and stirred at RT for 7 h. After thereaction was completion, Raney nickel was filtered, the resultingsolution was concentrated and purified by prep-HPLC to give1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea(10.0 mg, 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 7.28-7.26 (m, 2H), 7.11-7.09 (d, J=7.6 Hz, 1H), 7.05 (s, 1H)6.74-6.72 (t, J=11.6 Hz, 1H), 6.64-6.61 (t, J=11.6 Hz, 1H), 5.00-4.95(q, J=13.2 Hz, 1H), 4.46-4.44 (d, J=6 Hz, 2H), 4.30 (s, 1H), 4.22-4.19(m, 3H), 2.92-2.88 (m, 1H), 2.50-2.49 (m, 1H), 2.36-2.33 (m, 1H), 2.28(s, 3H), 2.00-1.97 (m, 1H). MS (ESI) m/z 460.7 [M+1]⁺.

Compound 45:(S)-1-(3-Chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea

To a solution of methyl 4-bromo-3-methylthiophene-2-carboxylate (5.0 g,21.37 mmol) in carbon tetrachloride (90 mL) was added N-bromosuccinimide(NBS) (4 g, 22.44 mmol) and Benzoyl peroxide (518 mg, 2.14 mmol). Themixture was stirred at 80° C. overnight. The solid was filtered and thefiltrate was diluted with sat. aq. NaHCO₃, then extracted with DCM. Thecombined organic layers were concentrated and purified on silica gel togive methyl 4-bromo-3-(bromomethyl)thiophene-2-carboxylate (5.03 g,75.4%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ: 7.49 (s, 1H), 4.91(s, 2H), 3.94 (s, 3H).

To a solution of methyl 4-bromo-3-(bromomethyl)thiophene-2-carboxylate(5.0 g, 16.026 mmol) and (S)-3-aminoazepan-2-one (2.46 g, 19.231 mmol)in DMF (80 mL) was added TEA (3.24 g, 32.052 mmol). The mixture wasstirred at RT for 2 h then diluted with water and extracted with EA.After removing the solvent under vacuum, the residue was purified onsilica gel to give (S)-methyl4-bromo-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate (3.20g, 55.5%) as a white solid. MS (ESI) m/z 361.4 [M+H]⁺.

To a solution of (S)-methyl4-bromo-3-(((2-oxoazepan-3-yl)amino)methyl)thiophene-2-carboxylate (3.16g, 8.778 mmol) in ACN (50 mL) was added Trimethylaluminium (1 M intoluene) (52.7 mL) slowly at 0° C. under nitrogen. The mixture wasstirred at RT overnight. It was quenched with saturated ammoniumchloride, then extracted with EA. The organic layers were washed withwater, brine, dried over Na₂SO₄, evaporated to give(S)-3-bromo-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (2.05g, 71.1%) as a yellow solid. MS (ESI) m/z 328.9 [M+H]⁺.

To a solution of(S)-3-bromo-5-(2-oxoazepan-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (1.2g, 3.658 mmol) in DMF (36 mL) was addedtris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃] (520 mg, 0.548mmol), zinc cyanide (516 mg, 4.390 mmol) and1,1′-bisdiphenylphosphinoferrocene [dppf] (650 mg, 1.208 mmol). Themixture was stirred at 150° C. for 1 h in a microwave under nitrogenatmosphere. It was concentrated to afford a residue, which was purifiedon silica gel to give(S)-6-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carbonitrile(630 mg, 59.6%) as a grey solid.

To a solution of(S)-6-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carbonitrile(580 mg, 2.109 mmol) in fluorobenzene/DMSO (30 mL/5 mL) was addedDess-Martin reagent (2.68 g, 6.327 mmol). The mixture was stirred to 80°C. overnight. The mixture was cooled to RT and 20 mL of a saturatedsodium thiosulfate solution was added followed by stirring for 5 min.The mixture was extracted with DCM (30 mL×2) and the combined solutionwas washed with 10% aq. sodium thiosulfate/aq. NaHCO₃ (1:1 mixture) (50mL) and brine (50 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated to afford the crude product which waspurified on silica gel to give(S)-5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carbonitrile(221 mg, 33.4%) as a yellow solid. MS (ESI) m/z 290.0 [M+H]⁺.

To a solution of(S)-5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carbonitrile(100 mg, 0.346 mmol) in THF (4 mL) was added Raney nickel (10 mg) andDi-tert-butyl dicarbonate (150 mg, 0.692 mmol). The suspension wasstirred at RT under hydrogen atmosphere for 3 h. LC-MS showed thestarting material was consumed and the desired product was detected. Themixture was filtered and the filtrate was concentrated to give crudeproduct, which was purified by prep-TLC in EA to give(S)-tert-butyl((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)carbamate(78.5 mg, 57.7%) as a yellow solid. MS (ESI) m/z 395.0 [M+H]⁺.

To a solution of (S)-tert-butyl((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)carbamate(38 mg, 0.097 mmol) in DCM (2.4 mL) at 0° C. was added2,2,2-trifluoroacetic acid (0.6 mL). The mixture was stirred at RT for 1h. The solvent was removed to give the crude product (28.3 mg, 100%) asa yellow oil.

To a solution of crude product (28.3 mg, 0.097 mmol) in THF (4 mL) wasadded TEA (24.4 mg, 0.242 mmol) and2-chloro-4-isocyanato-1-methylbenzene (19.4 mg, 0.116 mmol). The mixturewas stirred at RT for 2 h. LC-MS showed the starting material wasconsumed and the desired product was detected. The solvent was removedto give the crude product, which was purified by prep-TLC in EA to give(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea(30.0 mg, 67.4%) as a white solid. MS (ESI) m/z 460.7 [M+H]⁺. ¹H NMR(DMSO-d₆, 400 MHz) δ: 10.70 (s, 1H), 8.69 (s, 1H), 7.77 (s, 1H), 7.64(d, J=2.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8.0, 2.0 Hz, 1H),6.83 (t, J=5.6 Hz, 1H), 5.14 (dd, J=11.2, 5.6 Hz, 1H), 4.45 (d, J=8.4Hz, 2H), 4.32 (d, J=5.6 Hz, 2H), 3.10-3.01 (m, 1H), 2.56 (d, J=18.8 Hz,1H), 2.23 (s, 3H), 2.20-1.97 (m, 3H), 1.80-1.76 (m, 1H).

Compound 46:1-(6-Chloro-5-methylpyridin-2-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of 6-chloro-5-methylpyridin-2-amine (25.6 mg, 0.18 mmol)in DCM (4 mL) was added sodium hydride (4.3 mg, 0.18 mmol) at 0° C., theresulting solution was warmed to RT and stirred for 0.5 h, then the4-Nitrophenyl chloroformate (36.2 mg, 0.18 mmol) was added into themixture, and the mixture was stirred at RT for 1 h. TLC showed4-nitrophenyl (6-chloro-5-methylpyridin-2-yl)carbamate had formed, whichwas used directly to next step.

The crude 4-nitrophenyl (6-chloro-5-methylpyridin-2-yl)carbamate in DCM(4 mL) was added3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroactic acid salt (51.5 mg, 0.18 mmol), followed by TEA (36mg, 0.36 mmol). The resulting solution was stirred at RT for 2 h. Thereaction was concentrated to give the crude product, which was purifiedby prep-HPLC to give1-(6-chloro-5-methylpyridin-2-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(66.7 mg, 80.6%) as a white solid. MS (ESI) m/z 448.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.49 (s, 1H), 7.88 (s, 1H), 7.68 (d,J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.47 (t, J=5.2 Hz, 1H), 5.01 (dd,J=8.8, 14.0 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.27 (q, J=46.4 Hz, 2H),2.92-2.83 (m, 1H), 2.60-2.56 (m, 1H), 2.33-2.27 (m, 1H), 2.23 (s, 3H),2.02-1.96 (m, 1H).

Compound 47:1-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-isopropyl-4-methylphenyl)urea

To a solution of 3-isopropyl-4-methylaniline (27.5 mg, 0.18 mmol) in DCM(4 mL) was added 4-Nitrophenyl chloroformate (36.2 mg, 0.18 mmol) at RTand stirred for 1 h. Then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroactic acid salt (50.2 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The resulting solution was stirred at RT for2 h. The reaction was concentrated to give the crude product, which waspurified by prep-HPLC to give1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-isopropyl-4-methylphenyl)urea(25.1 mg, 29.9%) as a white solid. MS (ESI) m/z 455.1[M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.51 (s, 1H), 7.86 (s, 1H), 7.20 (d,J=2.0 Hz, 1H), 7.14 (dd, J=6.0, 8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H),6.67 (t, J=6.0 Hz, 1H), 5.01 (dd, J=8.4, 13.6 Hz, 1H), 4.42 (d, J=5.6Hz, 2H), 4.39 (q, J=43.2 Hz, 2H), 3.06-2.99 (m, 1H), 2.93-2.84 (m, 1H),2.57 (d, J=17.6 Hz, 1H), 2.32-2.23 (m, 1H), 2.19 (s, 3H), 2.00-1.96 (m,1H), 1.13 (d, J=6.8 Hz, 6H).

Compound 48:1-(3-Chloro-5-isopropyl-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of 3-chloro-5-isopropyl-4-methylaniline (32.9 mg, 0.18mmol) in DCM (4 mL) was added 4-Nitrophenyl chloroformate (36.2 mg, 0.18mmol) at RT and stirred for 1 h. Then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroactic acid salt (50.2 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The resulting solution was stirred at RT for2 h. The reaction was concentrated to give the crude product, which waspurified by prep-HPLC to give1-(3-chloro-5-isopropyl-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(15.9 mg, 17.7%) as a white solid. MS (ESI) m/z 489.1[M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.76 (s, 1H), 7.87 (s, 1H), 7.54 (d,J=2.0 Hz, 1H), 7.09 (s, 1H), 6.79 (t, J=6.0 Hz, 1H), 5.02 (dd, J=8.4,13.2 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H), 4.27 (q, J=42.8 Hz, 2H), 3.15-3.06(m, 1H), 2.94-2.83 (m, 1H), 2.57 (d, J=12.0 Hz, 1H), 2.32-2.27 (m, 1H),2.25 (s, 3H), 2.03-1.94 (m, 1H), 1.14 (d, J=6.8 Hz, 6H).

Compound 49:1-(5-Chloro-2,4-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of 5-chloro-2,4-dimethylaniline (28.6 mg, 0.18 mmol) inDCM (4 mL) was added 4-nitrophenyl chloroformate (36.2 mg, 0.18 mmol) atRT and stirred for 1 h. Then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroactic acid salt (50.2 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The resulting solution was stirred at RT for2 h. The reaction was concentrated to give the crude product, which waspurified by prep-HPLC to give1-(5-chloro-2,4-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(27.8 mg, 32.7%) as a white solid. MS (ESI) m/z 461.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 7.89 (s, 1H), 7.86 (d, J=3.2 Hz,2H), 7.18 (t, J=6.0 Hz, 1H), 7.10 (s, 1H), 5.02 (dd, J=8.4, 13.6 Hz,1H), 4.45 (d, J=5.2 Hz, 2H), 4.27 (q, J=44.8 Hz, 2H), 2.94-2.85 (m, 1H),2.58 (d, J=17.2 Hz, 1H), 2.34-2.27 (m, 1H), 2.22 (s, 3H), 2.13 (s, 3H),2.04-1.97 (m, 1H).

Compound 50:1-(3-Chloro-4-methylphenyl)-3-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)urea

To a stirred solution of tert-butyl 4-methylthiophene-3-carboxylate (3.0g, 15 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide(NBS) (2.83 g, 16 mmol) and benzoyl peroxide (1.83 g, 7.5 mmol). Themixture was stirred at 90° C. for 4 h then cooled to RT, filtered,evaporated, and purified on silica gel (petroleum ether) to givetert-butyl 4-(bromomethyl)thiophene-3-carboxylate (1.86 g, 44%) as acolorless oil. ¹H NMR (300 MHz, DMSO-d₆) δ 8.22 (d, J=4.0, 1H), 7.73 (d,J=4.0, 1H), 4.84 (s, 2H), 1.50 (s, 9H).

To a stirred solution of tert-butyl4-(bromomethyl)thiophene-3-carboxylate (1.83 g, 6.74 mmol) in DMF (4 mL)was added 3-aminopiperidine-2,6-dione hydrochloride salt (1.66 g, 10.08mmol) and TEA (3 mL). The mixture was stirred at 80° C. for 4 h. Thenthe reaction was cooled to RT, diluted with water, and extracted withEA. The organic layers were washed with brine, dried over Na₂SO₄,evaporated under vacuum, and purified on silica gel (petroleum/EA=l/1)to give tert-butyl4-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylate (750mg, 34%) as a blue oil. MS (ESI) m/z 325.0 [M+H]⁺.

To a stirred solution of tert-butyl4-(((2,6-dioxopiperidin-3-yl)amino)methyl) thiophene-3-carboxylate (750mg, 2.3 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture wasstirred at RT overnight then concentrated to give4-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylic acid,used crude in the next step. MS (ESI) m/z 269.0 [M+H]⁺.

To a stirred solution of4-(((2,6-dioxopiperidin-3-yl)amino)methyl)thiophene-3-carboxylic acid(2.3 mmol) in DMF (10 mL) was added DIEA (1.3 mL) and2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (1.3 g, 3.45 mmol). The mixture was stirredat RT for 2 h then water and DCM were added. The organic layer wasfiltered to give3-(4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione (400 mg,69%) as a white solid. MS (ESI) m/z 251.0 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d6) δ 10.97 (s, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 5.05-4.99 (m, 1H),4.25 (q, J=15.9 Hz, 2H), 2.61-2.59 (m, 1H), 2.55-2.54 (m, 1H), 2.38-2.33(m, 1H), 2.00-1.98 (m, 1H).

To a stirred solution of fuming nitric acid (5 mL) was added3-(4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione (350 mg,1.4 mmol) at 0° C. The mixture was stirred at 0° C. for 5 h then pouredinto ice water, and the pH was adjusted to 2 with IM NaOH solution. Themixture was filtered to give3-(1-nitro-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(250 mg, 61%) as a pink solid. MS (ESI) m/z 295.9 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.50 (s, 1H), 5.05 (dd, J=5.2, 13.6 Hz,1H), 4.60 (q, J=18.4 Hz, 2H), 2.91-2.84 (m, 1H), 2.60-2.55 (m, 1H),2.46-2.42 (m, 1H), 2.00-1.96 (m, 1H).

To a stirred solution of3-(1-nitro-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(100 mg, 0.34 mmol) in THF (8 mL) was added Raney nickel (50 mg). Themixture was stirred at RT overnight under hydrogen then filtered andconcentrated under vacuum to give3-(1-amino-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione,which was used crude for the next step. MS (ESI) m/z 266.0 [M+H]⁺.

To a stirred solution of3-(1-amino-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(0.34 mmol) in THF (4 mL) was added2-chloro-4-isocyanato-1-methylbenzene (86 mg, 0.51 mmol). The mixturewas stirred at RT for 4 h then evaporated under vacuum and purified byprep-HPLC to give1-(3-chloro-4-methylphenyl)-3-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)urea(18 mg, 12%) as a white solid. MS (ESI) m/z 433.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.79 (s, 1H), 8.93 (s, 1H), 7.68 (s, 1H),7.42 (s, 1H), 7.25 (s, 1H), 5.00 (dd, J=4.8, 13.6 Hz, 1H), 4.21 (q,J=15.2 Hz, 2H), 2.91-2.84 (m, 1H), 2.61-2.56 (m, 1H), 2.36-2.32 (m, 1H),2.26 (s, 1H), 2.00-1.98 (m, 1H).

Compound 51:(S)-1-(3-Chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea

To a solution of (S)-tert-butyl((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)carbamate(60 mg, 0.153 mmol) in DCM (3.6 mL) at 0° C. was added2,2,2-trifluoroacetic acid (0.9 mL). The mixture was stirred at RT for 1h. The solvent was removed under vacuum to give the crude product (44.7mg, 100%) as a yellow oil.

To a solution of crude product (44.7 mg, 0.153 mmol) in THF (3 mL) wasadded TEA (38.6 mg, 0.383 mmol) and2-chloro-4-(isocyanatomethyl)-1-methylbenzene (41.5 mg, 0.230 mmol). Themixture was stirred at RT for 2 h. The solvent was removed to give thecrude product, which was purified on silica gel to give(S)-1-(3-chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea(44.0 mg, 53.7%) as a white solid. MS (ESI) m/z 475.1 [M+H]⁺. ¹H NMR(DMSO-d₆, 400 MHz) δ: 10.71 (s, 1H), 7.70 (s, 1H), 7.26 (d, J=8.4 Hz,2H), 7.11 (d, J=7.6 Hz, 1H), 6.55 (t, J=5.2 Hz, 2H), 5.13 (t, J=8.4 Hz,1H), 4.44-4.18 (m, 6H), 3.06 (t, J=14.0 Hz, 1H), 2.56 (d, J=16.8 Hz,1H), 2.28 (s, 3H), 2.08-1.98 (m, 3H), 1.79-1.74 (m, 1H).

Compound 52:1-(3-Chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiourea

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(80 mg, 89% purity, 0.19 mmol) in DCM (4 mL) at 0° C. was added2,2,2-trifluoroacetic acid (1 mL). The mixture was warmed to RT andstirred for 2 h then concentrated under vacuum to afford3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoro-acetic acid salt (52.4 mg, 100%) as a white solid. MS(ESI) m/z 280 [M+H]⁺

To a solution of3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroacetic acid salt (52.4 mg, 0.19 mmol) in THF (3 mL) at 0°C. was added TEA (28.5 mg, 0.2818 mmol) and2-chloro-4-isothiocyanato-1-methylbenzene (37.9 mg, 0.21 mmol). Themixture was warmed to RT and stirred for 4 h then concentrated andpurified on silica gel eluting with MeOH in DCM from 0% to 10% to give1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiourea(60.6 mg, 69.8%) as a white solid. MS (ESI) m/z 463 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.74 (s, 1H), 8.36 (s, 1H), 7.88 (s, 1H),7.50 (s, 1H), 7.30 (t, J=8.0, 1H), 7.18-7.16 (m, 1H), 5.04-5.00 (m, 1H),4.86 (d, J=5.6, 2H), 4.28 (q, J=15.6, 41.6, 2H), 2.94-2.90 (m, 1H),2.61-2.57 (m, 1H), 2.32-2.29 (m, 4H), 2.00-1.97 (m, 1H).

Compound 53:1-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(6-methylpyridin-3-yl)urea

To a solution of 6-methylpyridin-3-amine (19.4 mg, 0.18 mmol) in DCM (4mL) was added 4-nitrophenyl chloroformate (36.2 mg, 0.18 mmol) at RT andstirred for 1 h. Then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroactic acid salt (50.2 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The resulting solution was stirred at RT for2 h then concentrated and purified by prep-HPLC to give1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(6-methylpyridin-3-yl)urea(19.6 mg, 25.7%) as a white solid. MS (ESI) m/z 414.1[M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.74 (s, 1H), 8.40 (d, J=2.8 Hz, 1H),7.87 (s, 1H), 7.75 (dd, J=5.6, 8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.88(t, J=6.0 Hz, 1H), 5.01 (dd, J=8.0, 13.2 Hz, 1H), 4.43 (d, J=4.8 Hz,2H), 4.27 (q, J=42.8 Hz, 2H), 2.93-2.83 (m, 1H), 2.45 (d, J=15.6 Hz,1H), 2.37 (s, 3H), 2.32-2.24 (m, 1H), 2.00-1.96 (m, 1H).

Compound 54:1-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea

To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) wasadded 4-methyl-3-(trifluoromethyl)aniline (100 mg, 0.51 mmol) dropwise,and the mixture was refluxed for 0.5 h. Then the mixture wasconcentrated, and the crude4-isocyanato-1-methyl-2-(trifluoromethyl)benzene was dissolved in THF (4ml) at RT, then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroacetic acid salt (51.5 mg, 0.18 mmol) was added, followedby TEA (36 mg, 0.36 mmol). The resulting solution was stirred at RT for2 h then the mixture was concentrated and purified by prep-HPLC to give1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea(35.9 mg, 40.5%) as a white solid. MS (ESI) m/z 481.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.93 (s, 1H), 7.87 (s, 1H), 7.85 (d,J=2.0 Hz, 1H), 7.48 (dd, J=6.4, 8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H),6.88 (t, J=6.4 Hz, 1H), 5.01 (dd, J=8.4, 13.2 Hz, 1H), 4.43 (d, J=6.0Hz, 2H), 4.39 (q, J=42.8 Hz, 2H), 2.93-2.84 (m, 1H), 2.59-2.55 (m, 1H),2.34-2.27 (m, 4H), 2.00-1.91 (m, 1H).

Compound 55:1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) wasadded a solution of 3-chloro-4-(trifluoromethyl)aniline (100 mg, 0.51mmol) and the mixture was refluxed at 80° C. for 0.5 h. After cooling toRT, the mixture was concentrated under vacuum and dissolved in THF (4mL), then3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroacetic acid (51.5 mg, 0.18 mmol) was added, followed byTEA (36 mg, 0.36 mmol). The solution was stirred at RT for 2 h thenconcentrated under vacuum and purified by prep-HPLC to give1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(18.6 mg, yield: 20.7%) as a white solid. MS (ESI) r/z 500.7, 502.6[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.35 (s, 1H), 7.87(s, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.43 (dd, J=7.2, 8.4 Hz, 1H), 7.11 (t,J=6.0 Hz, 1H), 5.01 (dd, J=8.0, 13.2 Hz, 1H), 4.40 (d, J=6.0 Hz, 2H),4.28 (q, J=41.6 Hz, 2H), 2.93-2.84 (m, 1H), 2.73-2.60 (m, 1H), 2.37-2.26(m, 1H), 2.07-1.97 (m, 1H).

Compound 56:2-(3-Chloro-4-methylphenyl)-N-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide

To a stirred solution of3-(1-nitro-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(100 mg, 0.34 mmol) in THF (8 mL) was added Raney nickel (50 mg). Themixture was stirred at RT overnight under hydrogen, then filtered andconcentrated to give3-(1-amino-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione,which was used in the next step without further purification. MS (ESI)m/z 266.0 [M+H]⁺.

To a stirred solution of3-(1-amino-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(0.34 mmol) and 2-(3-chloro-4-methylphenyl)acetic acid (60 mg, 0.32mmol), TEA (0.1 mL) in DCM (4 mL) was dropwise added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P)(0.1 mL) at −10° C. The mixture was stirred at RT for 5 h then quenchedwith sat. aq. NaHCO₃ and extracted with EA. The organic layer was washedwith brine, dried over Na₂SO₄, evaporated, and purified by prep-HPLC togive2-(3-chloro-4-methylphenyl)-N-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide(10 mg, 7%) as a yellow solid. MS (ESI) m/z 432.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 11.39 (s, 1H), 10.99 (s, 1H), 7.45 (s, 1H), 7.37 (s,1H), 7.30 (d, J=7.6 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 5.01 (dd, J=5.2,8.8 Hz, 1H), 4.25 (q, J=8.8 Hz, 2H), 3.69 (s, 2H), 2.90-2.85 (m, 1H),2.61-2.57 (m, 1H), 2.30-2.26 (m, 1H), 2.25 (s, 1H), 2.03-1.98 (m, 1H).

Compound 57:(S)-1-(6-Chloro-5-methylpyridin-2-yl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea

To a solution of 6-chloro-5-methylpyridin-2-amine (25.6 mg, 0.18 mmol)in DCM (4 mL) was added sodium hydride (4.3 mg, 0.18 mmol) at 0° C. Thesolution was warmed to RT and stirred for 0.5 h. 4-Nitrophenylchloroformate (36.2 mg, 0.18 mmol) was added, and the mixture wasstirred for 1 h then concentrated under vacuum to give crude4-nitrophenyl (6-chloro-5-methylpyridin-2-yl)carbamate, which was useddirectly to the next step.

To the solution of crude 4-nitrophenyl(6-chloro-5-methylpyridin-2-yl)carbamate in DCM (4 mL) was added(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (70.3 mg, 0.18 mmol), followedby TEA (36 mg, 0.36 mmol). The mixture was stirred at RT for 2 h thenconcentrated and purified by prep-HPLC to give(S)-1-(6-chloro-5-methylpyridin-2-yl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea(26.7 mg, yield: 33.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.71 (s, 1H), 9.49 (s, 1H), 7.88 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.58(d, J=8.4 Hz, 1H), 7.48 (t, J=5.6 Hz, 1H), 5.14 (dd, J=6.8, 12.0 Hz,1H), 4.51 (d, J=6.0 Hz, 2H), 4.39 (d, J=2.4 Hz, 2H), 3.09-3.01 (m, 1H),2.55 (d, J=16.8 Hz, 1H), 2.23 (s, 3H), 2.16-1.97 (m, 3H), 1.82-1.79 (m,1H). MS (ESI) m/z=461.7, 463.7[M+H]⁺.

Compound 58:(S)-2-((3-(4-((4-((3-(N-(tert-Butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino)—N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide

To a solution of (S)-tert-butyl((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(500 mg, 0.254 mmol) in DCM (4 mL) was added 2,2,2-trifluoroacetic acid(2 mL) at RT. The mixture was stirred for 0.5 h. The solvent was removedto give(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoro-acetic acid salt (372 mg, crude), which was useddirectly for the next step.

(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione2,2,2-trifluoro-acetic acid salt was dissolved in DCM (15 mL) and TEA(256 mg, 2.54 mmol) was added. The reaction was cooled to 0° C. andbromoacetyl chloride (241 mg, 1.53 mmol) was added. The mixture wasstirred at RT for 1 h. The solvent was removed and the residue waspurified on silica gel eluting with EA/MeOH from 0% to 8% to give(S)-2-bromo-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(478 mg, 90.1%) as a yellow oil. MS (ESI) m/z 414.1, 416.1 [M+1, M+3]⁺.

To a solution of3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)—N-(tert-butyl)benzenesulfinamide2,2,2-trifluoroacetic acid salt (117.0 mg, 0.24 mmol) in DMF (5 mL) wasadded DIEA (61.9 mg, 0.48 mmol), followed by(S)-2-bromo-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(100 mg, 0.24 mmol). The suspension was heated at 60° C. for 2 h. Thesolvent was removed and the residue was purified by prep-HPLC to give(S)-2-((3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino)—N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(14.6 mg, 7.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s,1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.50 (t, J=6.4 Hz, 1H), 8.15-8.12 (m,2H), 7.90 (s, 1H), 7.85 (s, 1H), 7.55-7.47 (m, 6H), 6.77 (d, J=9.2 Hz,2H), 5.12 (dd, J=6.8, 11.6 Hz, 1H), 4.43 (d, J=6.0 Hz, 2H), 4.35 (d,J=4.4 Hz, 2H), 3.95 (t, J=6.4 Hz, 1H), 3.14 (s, 2H), 3.07-2.99 (m, 1H),2.62 (t, J=6.8 Hz, 2H), 2.57-2.55 (m, 2H), 2.38-2.34 (m, 1H), 2.12 (s,3H), 2.02-1.96 (m, 2H), 1.93-1.78 (m, 3H), 1.11 (s, 9H). MS (ESI) m/z818.2 [M+H]⁺.

Compound 59:2-((3-(4-((4-((3-(N-(tert-Butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino)—N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide

To a solution of3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroacetic acid salt in DCM (5 mL) was added TEA (26.5 mg,0.262 mmol). The mixture was cooled to 0° C. then bromoacetyl chloride(25 mg, 0.157 mmol) was added. The mixture was stirred at RT for 2 h.The solvent was removed under vacuum and the residue was purified onsilica gel eluting with DCM/MeOH from 0% to 7% to give2-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(25 mg, 47.7%) as a white solid. MS (ESI) m/z 400.1, 402.1 [M+H, M+3]⁺.

To a solution of3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)—N-(tert-butyl)benzenesulfonamide2,2,2-trifluoroacetic acid salt (30.3 mg, 0.0625 mmol) in DMF (2 mL) wasadded K₂CO₃ (17.4 mg, 0.125 mmol), followed by2-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(25 mg, 0.0625 mmol). The suspension was heated at 50° C. for 3 h. Thesolvent was removed and the residue was purified by prep-HPLC to give2-((3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)amino)—N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(14.0 mg, 27.9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s,1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.49 (t, J=5.6 Hz, 1H), 8.13 (s, 2H),7.90 (s, 1H), 7.85 (s, 1H), 7.55-7.49 (m, 5H), 6.78 (d, J=8.8 Hz, 2H),4.99 (dd, J=4.8, 13.6 Hz, 1H), 4.41 (d, J=5.6 Hz, 2H), 4.30-4.15 (m,3H), 3.95 (t, J=6.0 Hz, 2H), 3.15 (s, 2H), 2.91-2.82 (m, 1H), 2.64-2.54(m, 4H), 2.33-2.26 (m, 1H), 2.12 (s, 3H), 1.97-1.91 (m, 1H), 1.84-1.80(m, 1H), 1.24 (s, 9H). MS (ESI) m/z 803.7 [M+H]⁺.

Compound 60:2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4—((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (40 mg, 0.1 mmol) in DMF(5 mL) at RT was added tert-butyl (4-aminobutyl)carbamate (22.4 mg, 0.12mmol), followed by2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (57 mg, 0.15 mmol) and DIEA (25.8 mg, 0.2mmol). The mixture was stirred at RT for 10 h. The reaction was dilutedwith water (5 mL) and extracted with DCM (10 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to give thecrude (S)-tert-butyl(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)butyl)carbamate(62 mg) as a white solid. MS (ESI) m/z 571.3[M+1]⁺.

To a solution of (S)-tert-butyl(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)butyl)carbamate(62 mg, 0.1 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (1mL) at RT. The mixture was stirred for 2 h. The solvent was removed togive(S)—N-(4-aminobutyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide2,2,2-trifluoroacetic acid salt (50 mg, crude) which was used directlyfor the next step. MS (ESI) m/z 471.3 [M+1]⁺.

To a solution of(S)—N-(4-aminobutyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide2,2,2-trifluoroacetic acid salt (47 mg, 0.1 mmol) in DMF (4 mL) wasadded K₂CO₃ (27.6 mg, 0.2 mmol), followed by2-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(60 mg, 0.15 mmol). The mixture was heated at 50° C. for 2 h thenconcentrated under vacuum and purified by prep-HPLC to give2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4—((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide(8.5 mg, 12.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (t,J=5.6 Hz, 1H), 8.20 (t, J=5.6 Hz, 1H), 7.84 (s, 1H), 7.49-7.40 (m, 4H),5.00 (dd, J=4.0, 12.4 Hz, 1H), 4.51 (t, J=7.2 Hz, 1H), 4.41 (d, J=5.6Hz, 2H), 4.30-4.15 (m, 3H), 3.26-3.21 (m, 4H), 3.11 (s, 3H), 2.92-2.82(m, 1H), 2.58 (s, 3H), 2.61-2.56 (m, 2H), 2.34-2.25 (m, 1H), 2.00-1.94(m, 2H), 1.61 (s, 3H), 1.44 (s, 4H). MS (ESI) m/z 789.6 [M+H]⁺.

Compound 61:(S)—N-(tert-Butyl)-3-((2-((4-(3-(3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)propoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide

To a solution of(S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt in DCM (5 mL) was added TEA(12.7 mg, 0.127 mmol). The mixture was cooled to 0° C., then4-nitrophenyl carbonochloridate (26 mg, 0.127 mmol) was added. Themixture was stirred at RT for 2 h and concentrated under vacuum to give(S)-4-nitrophenyl((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(70 mg, crude) as a yellow gum. MS (ESI) m/z 459.1[M+1]⁺.

To a solution of (S)-4-nitrophenyl((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(70 mg, crude, 0.127 mmol) in DCM (4 mL) was added TEA (26 mg, 0.254mmol), then3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)—N-(tert-butyl)benzenesulfonamide(62 mg, 0.127 mmol) was added. The mixture was stirred at RT for 2 hthen concentrated and purified on silica gel eluting with DCM/MeOH from0% to 9% and further purification by prep-HPLC to give(S)—N-(tert-butyl)-3-((2-((4-(3-(3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)propoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide(15.2 mg, 14.9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s,1H), 8.78 (s, 1H), 8.55 (s, 1H), 8.14 (s, 2H), 7.91 (s, 1H), 7.84 (s,1H), 7.56-7.49 (m, 5H), 6.80 (d, J=9.2 Hz, 2H), 6.54 (t, J=4.8 Hz, 1H),6.18 (t, J=5.6 Hz, 1H), 5.14 (dd, J=5.2, 12.4 Hz, 1H), 4.41-4.31 (m,4H), 3.92 (t, J=5.6 Hz, 2H), 3.20-3.17 (m, 3H), 3.09-3.01 (m, 2H),2.68-2.58 (m, 1H), 2.17 (s, 3H), 2.09-1.98 (m, 2H), 1.84-1.77 (m, 2H),1.13 (s, 9H). MS (ESI) m/z 803.7 [M+1]⁺.

Compound 62:N-(tert-Butyl)-3-((2-((4-(3-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)propoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide

To a solution of tert-butyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate(55 mg, 0.094 mmol) in DCM (5 mL) at RT was added 2,2,2-trifluoroaceticacid (1 mL). The mixture was stirred for 2 h. The solvent was removed togive3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)—N-(tert-butyl)benzenesulfonamide2,2,2-trifluoroacetic acid salt (60 mg, crude), which was used directlyfor the next step.

3-((2-((4-(3-aminopropoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)—N-(tert-butyl)benzenesulfonamide2,2,2-trifluoroacetic acid salt (60 mg, crude) was dissolved in DCM (5mL) and TEA (18.9 mg, 0.188 mmol) was added. The suspension was stirredat RT for 5 min. Then 4-nitrophenyl carbonochloridate (18.9 mg, 0.094mmol) was added and the mixture was stirred at RT for 3 h. The solventwas removed to give crude 4-nitrophenyl (3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate (70 mg) as a yellow gum,which was used directly for the next step. MS (ESI) m/z 651.1[M+1]⁺.

To a solution of tert-butyl((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)carbamate(40 mg, 0.105 mmol) in DCM (5 mL) was added TFA (1 mL) at RT. Themixture was stirred for 1 h. The solvent was removed to give3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroacetic acid salt (50 mg, crude) which was used directlyfor the next step.

3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione2,2,2-trifluoroacetic acid salt was dissolved in DCM (5 mL) and TEA (21mg, 0.21 mmol) was added. 4-nitrophenyl(3-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenoxy)propyl)carbamate(70 mg, crude) was added and the mixture was stirred at RT for 3 h. Thesolvent was removed under vacuum and the residue was purified on silicagel eluting with DCM/MeOH from 0% to 7% to give crude compound. It waspurified by prep-TLC (DCM/MeOH=10/1) to giveN-(tert-butyl)-3-((2-((4-(3-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)propoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide(20 mg, 24.2%) as a white solid. MS (ESI) m/z 789.7 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.78 (s, 1H), 8.54 (s, 1H), 8.14 (s, 1H),8.12 (s, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.53 (d, J=8.4Hz, 2H), 7.48 (t, J=4.4 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.52 (t, J=4.8Hz, 1H), 6.17 (t, J=6.0 Hz, 1H), 5.01 (dd, J=4.4, 13.6 Hz, 1H), 4.33 (d,J=6.0 Hz, 2H), 4.29-4.14 (m, 2H), 3.91 (t, J=6.0 Hz, 2H), 3.18-3.13 (m,2H), 2.94-2.83 (m, 1H), 2.59-2.55 (m, 1H), 2.34-2.22 (m, 1H), 2.12 (s,3H), 1.98-1.95 (m, 1H), 1.81-1.77 (m, 2H), 1.12 (s, 9H).

Compound 63:2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4—((2-(((5-((S)-2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide

To a solution of(S)-2-bromo-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide(42 mg, 0.088 mmol) in DMF (4 mL) was added K₂CO₃ (36.4 mg, 0.264 mmol),followed by(S)—N-(4-aminobutyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(44 mg, 0.106 mmol). The suspension was heated at 50° C. for 4 h. Thesolvent was removed and the residue was purified by prep-TLC(DCM/MeOH=10/1) to give2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4—((2-(((5-((S)-2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide(17 mg, 24.0%) as a white solid. MS (ESI) m/z 804.3[M+H]⁺1H NMR (400MHz, DMSO-d₆) δ 10.72 (s, 1H), 8.57 (t, J=5.2 Hz, 1H), 8.20 (t, J=6.0Hz, 1H), 7.85 (s, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H),5.13 (dd, J=5.2, 12.4 Hz, 1H), 4.51 (t, J=6.4 Hz, 1H), 4.44 (d, J=5.6Hz, 2H), 4.36 (s, 2H), 3.28-3.22 (m, 4H), 3.17 (s, 2H), 3.09 (s, 2H),3.05-3.00 (m, 1H), 2.61-2.50 (m, 2H), 2.58 (s, 3H), 2.40 (s, 3H),2.19-2.13 (m, 1H), 2.07-1.98 (m, 2H), 1.82-1.75 (m, 1H), 1.61 (s, 3H),1.46 (s, 4H).

Compound 64:3-(3-Cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

To a solution of methyl 4-bromo-3-methylthiophene-2-carboxylate (5.0 g,21.37 mmol) in carbon tetrachloride (90 mL) at RT was addedN-bromosuccinimide (NBS) (4 g, 22.44 mmol) and dibenzoyl peroxide (BPO)(518 mg, 2.14 mmol). The mixture was stirred at 80° C. overnight. Thereaction was cooled to RT and filtered. The filtrate was diluted withsat. aq. NaHCO₃, then extracted with dichloromethane. The combinedorganic layers were dried over Na₂SO₄, filtered, concentrated, andpurified on silica gel eluting with petroleum to give methyl4-bromo-3-(bromomethyl)thiophene-2-carboxylate (4.81 g, 72.1%) as awhite solid ¹H NMR (CDCl₃, 300 MHz) δ: 7.47 (s, 1H), 4.89 (s, 2H), 3.92(s, 3H).

To a solution of methyl 4-bromo-3-(bromomethyl)thiophene-2-carboxylate(4.80 g, 15.35 mmol) and tert-butyl 4,5-diamino-5-oxopentanoate (4.41 g,18.46 mmol) in DMF (80 mL) was added TEA (3.11 g, 30.770 mmol). Themixture was stirred at RT overnight then diluted with water andextracted with EA. The organic layers were concentrated, and the residuewas purified on silica gel eluting with EA in petroleum (50%) to givemethyl3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bromothiophene-2-carboxylate(5.92 g, 81.7%) as a white solid.

To a solution of methyl3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bromothiophene-2-carboxylate(1 g, 2.12 mmol) in tetrahydrofuran (20 mL) was added lithium hydroxide(5.3 mL, 0.56 N) slowly. The suspension was stirred at RT for 2 h thenconcentrated. Water was added, and the mixture was extracted with EA.The water phase was adjusted to a pH of 5-6 using HCl (1 N) dropwisethen concentrated to give the crude3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bromothiophene-2-carboxylicacid (968 mg, 100%) as a white solid, used directly in the next step.

To a solution of3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bromothiophene-2-carboxylicacid (968 mg, 2.3 mmol) in DMF (20 mL) was added2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (1.31 g, 3.45 mmol) and DIEA (590 mg, 4.60mmol) at RT. The suspension was stirred at RT overnight. The mixture wasdiluted with water and extracted with EA. After removing the solventunder vacuum, the residue was washed with EA to give tert-butyl5-amino-4-(3-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate(461 mg, 48.2%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ: 7.56 (s,1H), 6.40 (s, 1H), 5.56 (s, 1H), 4.86-4.82 (m, 1H), 4.48 (d, J=18.4,1H), 4.28 (d, J=18.0, 1H), 2.37-2.10 (m, 1H), 1.43 (s, 9H).

To a solution of tert-butyl5-amino-4-(3-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate(400 mg, 0.99 mmol) in dioxane/water (12 mL/1.2 mL) was added2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (288 mg,1.49 mmol), tetrakis(triphenylphosphine)palladium [Pd(PPh₃)₄] (232 mg,0.20 mmol) and cesium carbonate (808 mg, 2.48 mmol). The atmosphere wasreplaced with nitrogen, and the mixture was stirred at 90° C. overnight.The mixture was then cooled to RT, concentrated, and diluted with waterand extracted with DCM. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated to give crude product, which waspurified on silica gel eluting with EA in petroleum (50% to 100%) togive tert-butyl5-amino-4-(3-(cyclopent-1-en-1-yl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate(302 mg, 77.8%) as a light-yellow solid. MS (ESI) m/z=391.0 [M+H]⁺.

To a solution of tert-butyl5-amino-4-(3-(cyclopent-1-en-1-yl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate(250 mg, 0.64 mmol) in THF (10 mL) at RT was added Pd/C (125 mg) and thesuspension was stirred for 5 days. The mixture was filtered throughcelite then concentrated under vacuum to afford tert-butyl5-amino-4-(3-cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate(251 mg, 100%) as a yellow solid. MS (ESI) m/z=393.2 [M+H]⁺.

To a solution of tert-butyl5-amino-4-(3-cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate(70 mg, 0.179 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid(1.5 mL) at 0° C. then the mixture was stirred at RT for 1 h. Thesolvent was removed under vacuum to give5-amino-4-(3-cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoicacid (60 mg, yield: 100%) as a crude solid.

To a solution of5-amino-4-(3-cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoicacid (60 mg, 0.179 mmol) in ACN (6 mL) was addedN,N′-carbonyldiimidazole (115.7 mg, 0.716 mmol) then the mixture wasrefluxed at 90° C. overnight. The solvent was removed under vacuum togive the crude product, which was purified on silica gel eluting with EAin petroleum (100%) to give3-(3-cyclopentyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(47.1 mg, 82.9%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.97(s, 1H), 7.65 (d, J=15.2, 1H), 5.00 (dd, J=12.8, 4.8 Hz, 1H), 4.41 (d,J=17.6, 1H), 4.25 (d, J=17.6, 1H), 3.09-3.00 (m, 1H), 3.00-2.84 (m, 1H),2.58 (d, J=16.4, 1H), 2.43-2.32 (m, 1H), 2.03-1.98 (m, 3H), 1.78-1.50(m, 6H). MS (ESI) m/z=393.2 [M+H]⁺.

Compound 65:1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

Compound 65 was prepared analogously to compounds previously describedherein. ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 8.75 (s, 1H), 7.66(s, 1H), 7.19-7.02 (m, 3H), 6.83 (t, J=6.0 Hz, 1H), 5.04-4.99 (m, 1H),4.49 (d, J=6.0 Hz, 2H), 4.33 (m, 2H), 2.89 (m, 1H), 2.58 (d, J=16.4,1H), 2.32-2.28 (m, 1H), 2.23 (s, 3H), 2.00-1.95 (m, 1H). MS (ESI)m/z=447 [M+H]⁺.

Compound 66:3-(1-cyclopentyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione

Compound 66 was prepared analogously to compounds previously describedherein. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 7.79 (s, 1H), 5.00(m, 1H), 4.32 (m, 2H), 3.23 (m, 1H), 2.89 (m, 1H), 2.56 (m, 1H), 2.36(m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 1.75 (m, 2H), 1.55-1.65 (m, 4H). MS(ESI) m/z=319 [M+H]⁺.

Cell-Based Assays

Frozen primary blood mononuclear cells (PBMCs) and frozen CD14+mobilized peripheral blood monocytes were purchased from AllCells. Cellswere quick thawed, and washed 1-time with RPMI-1640/10% FBS/1%Penicillin/1% Streptomycin and plated in 96-well plates at 200,000 cellsper well. Cells were pretreated with DMSO only, Compound 5013(lenolidamide) or the indicated compound for 1 h and then induced with100 ng/mL lipopolysaccharide (LPS) for 18-24 h. The supernatant wasanalyzed for IL-1 beta, IL-6, and TNF-α using Meso Scale assay accordingto manufacturer's protocol. The negative control wells were treated withDMSO.

For the IL-2 analysis, 96 well plates were precoated with 1 ug/mLanti-human CD3 antibody (OKT3, eBioscience Inc.). After washing withPBS, compounds were added to the wells (50 μL/well) followed by PBMCsdiluted at 3-4 million cells/mL (150 μL/well). Plates were incubated for24 h and the supernatants collected for Mesoscale IL-2 analysis.

Compound activity was measured as fold difference from the DMSO control.IL-1-beta activity is shown in FIG. 1; IL-6 activity is shown in FIG. 2;TNF-α activity is shown in FIG. 3; and IL-2 activity is shown in FIG. 4.

PBMCs: AllCells PB003F, Normal Peripheral Blood MNC.

Media: RPMI 1640/10% FBS/1% Pen-Strep.

Compounds 2 and 8 reduced expression of IL-1-b in LPS-stimulated PBMCsby over 80%, relative to a just over 60% reduction with an equimolarconcentration of lenalidomide (FIG. 5). Compounds 2 and 8 also reducedIL-6 levels in LPS-stimulated PBMCs by 60-75%, compared with a below 60%reduction in expression for cells treated with lenalidomide (FIG. 6).Compounds 2 and 8 also reduced expression of TNF-α in LPS-stimulatedPBMCs by 60-75%, relative to a less than 60% reduction with an equimolarconcentration of lenalidomide (FIG. 7). Inhibition data for additionalcompounds are shown in Table 1.

TABLE 1 Protein Levels at Indicated Compound Concentration CompoundConcentration % Inhibition Fold Change No. (μM) IL-1β IL-6 TNF-α IL-2DMSO 0.1% 0% 0% 0% 1.0 1 5 25 0 22 0.8 2 5 88 31 65 1.9 3 10 0 0 0 0.9 410 0 0 0 0.7 5 10 0 1 0 1.4 6 10 14 8 16 1 7 10 60 47 41 1.7 8 10 80 7171 1 9 0.1 98 100 98 0 10 10 21 13 37 0.6 11 10 65 26 46 2.6 12 10 52 056 0.8 13 10 90 66 84 1.2 14 10 88 65 85 1.5 15 10 67 56 55 0.7 16 10 8051 78 2.2 17 10 4 14 26 1 18 10 36 32 48 0.9 19 10 79 78 59 4 20 10 5019 58 2.2 21 10 74 73 74 2.9 22 10 0 16 26 0.8 23 10 69 45 82 2 24 10 116 23 0.7 25 10 45 22 41 1.3 26 10 2 14 31 0.9 27 10 21 3 22 0.8 28 10 09 0 0.9 29 10 57 19 60 — 30 1 81 98 84 0.4 31 1 76 40 80 1.7 32 0.1 6765 62 0.8 33 0.1 95 99 95 0.3 34 1 70 39 69 1.6 35 1 44 16 39 1.4 36 140 38 33 0.8 37 1 4 3 6 1.1 38 1 84 94 87 0.6 39 1 24 0 18 1.4 40 1 3717 34 0.3 41 1 89 95 90 0.3 42 1 91 97 90 0.4 43 1 73 88 77 0.5 44 1 456 41 1 45 1 19 18 22 — 46 0.1 54 85 58 — 47 0.1 99 100 97 — 48 0.1 96100 92 — 49 0.1 61 87 62 — 50 1 14 0 1 — 51 1 38 5 49 — 52 0.1 98 100 95— 53 0.1 60 90 65 — 54 0.1 96 100 93 — 55 0.1 99 100 96 — 56 1 55 12 59— 57 1 42 32 44 — 58 10 82 53 92 1.9 59 10 45 10 81 1.8 60 1 91 95 930.2 61 10 53 11 66 0.8 62 10 51 15 63 — 63 10 27 1 34 — 64 10 22 8 45 —

TABLE 2 GSPT1 Protein Levels at 100 nM Compound Concentration CompoundGSPT1 Protein No. Levels DMSO 100.00 30 42.68  9 6.77 31 131.32 32 61.6933 5.90 34 84.88 35 112.06 37 123.56 38 49.00 39 87.44 40 46.04 41 55.2442 50.70 43 56.02 36 92.87 44 57.33 45 90.35 52 0.58 46 65.15 53 23.4747 0.64 54 2.25 48 1.46 55 1.51 49 11.93 57 265.24

TABLE 3 GSPT1 Protein Levels at 1 μM Compound Concentration CompoundGSPT1 Protein No. Levels DMSO 100.00 30 5.28  9 5.31 31 107.70 32 29.3433 5.50 34 37.47 35 44.46 37 153.84 38 5.52 39 95.98 40 39.98 41 6.40 428.44 43 14.23 36 32.62 44 53.61 45 22.34 52 1.05 46 4.73 53 6.18 47 2.6154 2.72 48 3.85 55 2.86 49 20.01 57 28.42Western Blot Analysis

Western Blot Protocol: Cell lines were grown in RPMI 1640 supplementedwith streptomycin, penicillin and 10% fetal bovine serum.

Cells were cultured at approximately 10⁶ cells per mL and incubated inDMSO or each of the indicated compounds for 6-8 h. Whole cell extractswere prepared using RIPA buffer according to manufacturer's protocol(Pierce). Briefly, 2×10⁶ cells were washed once in PBS, the cell pelletswere resuspended in RIPA buffer and allowed to incubate for 15 minuteson ice. Cells debris was removed by centrifugation and the cleared wholecell lysates were transferred to new tubes for further analysis.

For Western blot analysis, whole cell protein extracts were separated on4-12% SDS-polyacrylamide gels, transferred to nitrocellulose, and probedwith the indicated primary antibodies. Membranes were subsequentlywashed and probed with the appropriate IRDye secondary antibodies(LI-COR). The signal was detected using the Odyssey Imaging System(LI-COR).

The following antibodies were used in these studies:

-   -   β-actin: Mouse anti-b-Actin was obtained from Cell Signaling,        8H10D10 (Danvers, Mass.)    -   GSPT1: Rabbit anti-GSPT1 was obtained from Abcam, ab126090        (Cambridge, Eng.) CK1α goat polyclonal antibody: Santa Cruz        Biotechnology, sc-6477 (Santa Cruz, Calif.) Casein kinase 1        epsilon goat polyclonal antibody: Santa Cruz Biotechnology,        sc-6471 (Santa Cruz, Calif.)    -   Ikaros rabbit monoclonal antibody: Cell Signaling, #9034, D10E5        (Danvers, Mass.)    -   Donkey anti-goat IgG-HRP: Santa Cruz Biotechnology, sc-2056        (Santa Cruz, Calif.)    -   Goat anti-rabbit IgG-HRP: Cell Signaling, #7074 (Danvers, Mass.)    -   Goat anti-mouse IgG-HRP: Sigma, A4416 (St. Louis, Mo.)    -   Anti-eRF3/GSPT1 antibody: Abcam, ab126090 (Cambridge, Mass.)    -   β-Actin (8H10D10) mouse monoclonal antibody: Cell Signaling        Technology, #3700 (Danvers, Mass.)    -   IRDye 680RD Goat anti-rabbit antibody: LI-COR, 926-68071        (Lincoln, Nebr.)    -   IRDye 800CW Goat anti-mouse antibody: LI-COR, 926-32210        (Lincoln, Nebr.)        Cell Viability Assays

Molm-13 cells were cultivated in RPMI-1640 (10% FBS/1% pen-strep) andwere plated in white walled 96-well plates at 20,000 cells/well. H1048cells were cultured in DMEM:F12 media supplemented with 5% fetal bovineserum, insulin, transferrin, sodium selenite, hydrocortisone,β-estradiol, penicillin and streptomycin, and were plated in whitewalled 96-well plates at 20,000 cells/well. MDA-MB-231 cells werecultured in DMEM media supplemented with 10% fetal bovine serum,penicillin and streptomycin, and were plated in white walled 96-wellplates at 10,000 cells/well. Cells were treated with compound or DMSO(0.1%, control) and the cultures were incubated for 3 days at 37° C. and5% CO₂. Following the incubation period, 100 μL of CellTiterGlow (CTG)reagent (CellTiter-Glo® Luminescent Cell Viability Assay, Promega(Madison, Wis.)) was added to each well. Following a 10 min incubationwith shaking, luminescence was measured using a Victor WallacLuminometer.

Compound 9 reduced cell viability in H1048 cells at an IC₅₀concentration of 0.5 nM (FIG. 10A) and in Molm-13 at an approximate IC₅₀concentration of 3 nM (FIG. 10B). Cell viability data for additionalcompounds are shown in Tables 4-8.

TABLE 4 H1048 Cell Viability at 1 μM Compound Concentration Compound No.Cell Viability DMSO 100.00  9 7.50 30 8.55 31 84.29 32 10.62 33 8.76 3412.95 35 15.49 36 10.64 37 55.04 38 8.35 39 58.32 40 12.95 41 9.42 428.70 43 7.97 44 13.82 45 12.70 46 9.35 47 8.91 48 9.03 49 7.67 50 15.8351 94.94 52 9.22 53 8.51 54 8.11 55 7.63 56 29.12 57 12.36

TABLE 5 H1048 Cell Viability at 10 μM Compound Concentration CompoundNo. Cell Viability DMSO 100.00  9 7.93 30 8.34 31 26.82 32 10.77 33 8.2134 8.34 35 12.40 36 7.51 37 10.48 38 7.89 39 19.88 40 13.64 41 9.37 428.68 43 7.63 44 14.28 45 9.89 46 11.46 47 8.58 48 6.89 49 6.10 50 13.4052 10.30 51 24.09 53 8.09 54 6.12 55 7.94 56 26.33 57 8.70

TABLE 6 MOLM-13 Cell Viability at Indicated Compound ConcentrationsCompound No. Concentration (μM) % Inhibition DMSO 0.1% 0 1 10 6 2 10 323 10 0 4 10 0 5 10 24 6 10 0 7 10 24 8 10 42 9    0.003 50 10 10 18 1110 18 12 10 31 13 10 0 14 10 0 15 10 19 16 10 23 17 10 21 18 10 3 19 1029 20 10 19 21 10 16 22 10 23 23 10 34 24 10 26 25 10 20 26 10 0 27 10 028 10 0 29 10 10 30  1 50 31 10 12 32   0.5 25 33    0.003 50 34 10 9935 10 93 36 10 100 37 10 51 38   0.3 50 39 10 9 40    0.02 50 41   0.350 42   0.8 50 43 10 100 44   0.1 50 45  1 59 46   0.1 100 47   0.1 10048   0.1 100 49   0.1 100 50  1 41 51  1 0 52   0.1 99 53   0.1 100 54  0.1 100 55   0.1 100 56   0.1 10 57  1 45 58  6 50 59   2.8 50 60  0.2 50 61   2.8 50 62  1 71 63  >1* 50 64 10 13 *predicted value

TABLE 7 MDA-MB-231 Cell Viability at 1 μM Compound ConcentrationCompound No. Cell Viability DMSO 100.00 30 52.87  9 19.57 31 102.66 3291.23 33 21.72 34 102.35 35 99.01 37 105.62 38 54.70 39 105.43 40 57.7241 58.21 42 57.58 43 55.17 36 100.69 44 64.61 45 100.54 52 22.40 4629.04 53 27.59 47 21.76 54 22.60 48 22.17 55 20.16 49 24.33 56 107.79 50107.95 57 107.01 51 107.95

TABLE 8 MDA-MB-231 Cell Viability at 10 μM Compound ConcentrationCompound No. Cell Viability DMSO 100.00 30 26.30  9 19.05 31 107.39 3244.33 33 19.76 34 44.37 35 64.83 37 97.71 38 27.60 39 100.75 40 49.96 4129.98 42 30.53 43 23.74 36 53.36 44 56.46 45 46.69 52 20.54 46 24.07 5321.34 47 19.30 54 22.38 48 21.67 55 19.04 49 19.73 56 101.24 50 95.73 5751.97 51 102.80Pharmaceutical Compositions

Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous, or the like),0.1 mg to 100 mg of a water-soluble salt/soluble materialitself/solubilized complex of a compound of a preferred embodiment isdissolved in sterile water and then mixed with 10 mL of 0.9% sterilesaline. The mixture is incorporated into a dosage unit form suitable foradministration by injection.

Injectable Pharmaceutical Composition

To prepare an injectable formulation, 0.1 mg to 100 mg of a compound ofFormula II, 2.0 mL of NaOAc buffer solution (0.4 M), HCl (1 N) or NaOH(1 M) (q.s. to suitable pH), water (distilled, sterile) (q.s. to 20 mL)are mixed. All of the above ingredients, except water, are combined andstirred and if necessary, with slight heating if necessary. A sufficientquantity of water is then added.

Oral Pharmaceutical Composition

To prepare a pharmaceutical composition for oral delivery, 0.1 mg to 100mg of a compound of a preferred embodiment is mixed with 750 mg ofstarch. The mixture is incorporated into an oral dosage unit, such as ahard gelatin capsule, or 0.1 mg to 100 mg of compound is granulated withbinder solution such as starch solution along with suitable diluentssuch as microcrystalline cellulose or like, disintegrants such ascroscaramellose sodium, dry the resultant mixture and add lubricant andcompress into tablet which is suitable for oral administration.

Sublingual (Hard Lozenge) Pharmaceutical Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, 0.1 mg to 100 mg of a compound of a preferred embodimentis mixed with 420 mg of powdered sugar/mannitol/xylitol or such sugarsthat provide negative heat of solution to the system, 1.6 mL of lightcorn syrup, 2.4 mL distilled water, and 0.42 mL mint extract or otherflavorants. The mixture is blended and poured into a mold to form alozenge suitable for buccal administration.

Fast-Disintegrating Sublingual Tablet

A fast-disintegrating sublingual tablet is prepared by mixing 48.5% byweigh of a compound of a preferred embodiment, 20% by weight ofmicrocrystalline cellulose (KG-802), 24.5% by weight of either mannitolor modified dextrose or combination that help dissolve the compressedtablet faster in the mouth, 5% by weight of low-substitutedhydroxypropyl cellulose (50 μM), and 2% by weight of magnesium stearate.Tablets are prepared by direct compression (AAPS PharmSciTech. 2006;7(2):E41). The total weight of the compressed tablets is maintained at150 mg. The formulation is prepared by mixing the amount of the compoundof a preferred embodiment with the total quantity of microcrystallinecellulose (MCC) and mannitol/modified dextrose or combination, andtwo-thirds of the quantity of low-substituted hydroxypropyl cellulose(L-HPC) by using a three dimensional manual mixer (Inversina®,Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesiumstearate (MS) and the remaining one-third of the quantity of L-HPC areadded 30 seconds before the end of mixing.

Inhalation Pharmaceutical Composition

To prepare a pharmaceutical composition for inhalation delivery, 0.1 mgto 100 mg of a compound of a preferred embodiment is mixed with 50 mg ofanhydrous citric acid and 100 mL of 0.9% aq. NaCl. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Nebulizer Suspension Pharmaceutical Composition

In another embodiment, a compound of a preferred embodiment (0.1 mg to100 mg) is suspended in sterile water (100 mL); Span 85 (1 g) is addedfollowed by addition of dextrose (5.5 g) and ascorbic acid (10 mg).Benzalkonium chloride (3 mL of a 1:750 aqueous solution) is added andthe pH is adjusted to 7 with phosphate buffer. The suspension ispackaged in sterile nebulizers.

Transdermal Patch Pharmaceutical Composition

To prepare a pharmaceutical composition for transdermal delivery, 0.1 mgto 100 mg of a compound of a preferred embodiment is embedded in, ordeposited on, a patch with a single adhesive face. The resulting patchis then attached to the skin via the adhesive face for transdermaladministration.

Topical Gel Pharmaceutical Composition

To prepare a pharmaceutical topical gel composition, 0.1 mg to 100 mg ofa compound of a preferred embodiment is mixed with 1.75 g ofhydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropylmyristate and 100 mL of purified alcohol USP. The resulting gel mixtureis then incorporated into containers, such as tubes, which are suitablefor topical administration.

Ophthalmic Solution

To prepare a pharmaceutical ophthalmic solution composition, 0.1 mg to100 mg of a compound of a preferred embodiment is mixed with 0.9 g ofNaCl in 100 mL of purified water and filtered using a 0.2 micron filter.The resulting isotonic solution is then incorporated into ophthalmicdelivery units, such as eye drop containers, which are suitable forophthalmic administration.

Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 0.1 mg to 100 mg of acompound of a preferred embodiment is mixed with 30 mL of a 0.05Mphosphate buffer solution (pH 4.4). The solution is placed in a nasaladministrator designed to deliver 100 μl of spray for each application.

While the disclosure has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive. Thedisclosure is not limited to the disclosed embodiments. Variations tothe disclosed embodiments can be understood and effected by thoseskilled in the art in practicing the claimed disclosure, from a study ofthe drawings, the disclosure and the appended claims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas ‘known’, ‘normal’, ‘standard’, and terms of similar meaning shouldnot be construed as limiting the item described to a given time periodor to an item available as of a given time, but instead should be readto encompass known, normal, or standard technologies that may beavailable or known now or at any time in the future; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Moreover, any one of the above described embodiments can be used aloneor in combination with any one or more of the above describedembodiments. Furthermore, although the foregoing has been described insome detail by way of illustrations and examples for purposes of clarityand understanding, it is apparent to those skilled in the art thatcertain changes and modifications may be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention to the specific embodiments and examples describedherein, but rather to also cover all modification and alternativescoming with the true scope and spirit of the invention.

What is claimed is:
 1. A method of treating cancer associated with acytokine, aiolos, ikaros, helios, CKla, or GSPT1, comprisingadministering a compound of Formula (IIa) or a pharmaceuticallyacceptable salt thereof to a subject in need thereof,

wherein: R₁ and R₂ are each independently H, deuterium, hydroxyl,halogen, cyano, nitro, optionally substituted amino, optionallysubstituted C₁-C₆ alkoxy, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₃-_(C8) cycloalkyl, optionally substitutedC₆-C₁₀ aryl, optionally substituted 3 to 10-membered heterocyclyl, oroptionally substituted 5 to 10-membered heteroaryl; or one of _(R1) andR₂ is H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted amino, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-_(C6) alkyl, optionally substituted C₂-_(C6) alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-_(C10) aryl, optionallysubstituted 3 to 10-membered

heterocyclyl, optionally substituted 5 to 10-membered heteroaryl, orL-Y; and the other of R₁ and R₂ is optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 3to 10-membered heterocyclyl, optionally substituted 5 to 10-memberedheteroaryl, or L-Y;

provided that when one of R₁ and R2 is then the other R₁ and _(R2) isnot L-Y; R₅ is H, deuterium, or optionally substituted C₁-C₆ alkyl; n is2 or 3; each of Qa and Qb is independently C═O, C=S, or CH₂; X is CH₂ orC(═O); X₁ is H, deuterium, halogen, or optionally substituted C₁-C₆alkyl; m is 1, 2, 3, 4, or 5; X₂ is (CH₂)_(a), C═O, NH, or N—(optionallysubstituted C₁-_(C6) alkyl); X₃ is 0, NI-₂ or S; a is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, or 10; R₈ is optionally substituted C₃-C₁₀ cycloalkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to10-membered heteroaryl, optionally substituted 3 to 10-memberedheterocyclyl, optionally substituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl),optionally substituted C₆-C₁₀ aryl(C₁-_(C6) alkyl), optionallysubstituted 5 to 10 membered heteroaryl(C₁-C₆ alkyl), or optionallysubstituted 3 to 10 membered heterocyclyl(C₁-C₆ alkyl);

L is each Z₁ and Z₂ arc each is —CH₂₋; each R₆ is absent orindependently absent or C₁-C₆ alkyl; and each Y is independentlyselected from a group consisting of

wherein * represents the point of attachment to L.
 2. The method ofclaim 1, wherein n is 2; X₁ is H; R₅ is H; and Qa and Qb are each C═O.3. The method of claim 2, wherein one of R₁ and R₂ is hydrogen and theother of R₁ and R₂ is optionally substituted C₁-C₆ alkyl or optionallysubstituted C₃-C₈ cycloalkyl.
 4. The method of claim 2, wherein one ofR₁ and R2 is optionally substituted C₁-C₆ alkyl or H; and the other ofR₁ and R₂ is chloro, bromo, nitro, cyano, or optionally substitutedamino.
 5. The method of claim 1, wherein the cancer is leukemia,lymphoma, multiple myeloma, breast cancer, or lung cancer.
 6. A methodof treating cancer associated with a cytokine, aiolos, ikaros, helios,CK1α, or GSPT1, comprising administering a compound of Formula (IIb), ora pharmaceutically acceptable salt thereof to a subject in need thereof,

wherein: one of R₁ and R₂ is H, deuterium, hydroxyl, halogen, cyano,nitro, optionally substituted amino, optionally substituted C₁-C₆alkoxy, optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted 3 to 10-membered

heterocyclyl, optionally substituted 5 to 10-membered heteroaryl, orL-Y; and the other of R₁ and R₂ is optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 3to 10-membered heterocyclyl, optionally substituted 5 to 10-memberedheteroaryl, or L-Y;

provided that when one of R₁ and R₂ is then the other R₁ and R₂ is notL-Y; R₅ is H, deuterium, or optionally substituted C₁-C₆ alkyl; n is 2or 3; each of Qa and Qb is independently C═O, C=S, or CH₂; X is CH₂ orC(═O); X₁ is H, deuterium, halogen, or optionally substituted C₁-C₆alkyl; m is 1, 2, 3, 4, or 5; X₂ is (CH₂)α, C═O, NH, or N—(optionallysubstituted C₁-C₆ alkyl); X₃ is O, NH, or S; a is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; R₈ is optionally substituted C₃-C₁₀ cycloalkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to10-membered heteroaryl, optionally substituted 3 to 10-memberedheterocyclyl, optionally substituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl),optionally substituted C₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted5 to 10 membered heteroaryl(C₁-C₆ alkyl), or optionally substituted 3 to10 membered heterocyclyl(C₁-C₆ alkyl);

each Z₁ and Z₂ are each is CH₂—; each R₆ is independently absent orC₁-C₆ alkyl; and each Y is independently selected from a groupconsisting of

wherein * represents the point of attachment to the L group.
 7. Themethod of claim 6, wherein n is 2; X₁ is H; R₅ is H; and Qa and Qb areeach C═O.
 8. The method of claim 7, wherein one of R₁ and R₂ is

hydrogen and the other R₁ and R₂ is or L-Y.
 9. The method of claim 7,wherein R₁ is

and R₂ is H.
 10. The method of claim 9, wherein R₁ is and X2 is NH.


11. The method of claim 10, wherein R₈ is a phenyl group substitutedwith one or more substituents, each of which is independently selectedfrom the group consisting of halogen, unsubstituted C₁-C₆ alkyl, C₁-C₃alkoxy, and unsubstituted di(C₁-C₃ alkyl)amino; or a 5-6 memberedheteroaryl group substituted with one or more substituents each of whichis independently selected from the group consisting of halogen,unsubstituted C₁-C₆ alkyl, C₁-C₃ alkoxy, and unsubstituted di(C₁-C₃alkyl)amino.
 12. The method of claim 11, wherein R₈ is a phenyl groupsubstituted with unsubstituted C₁-C₆ alkyl and halogen, a phenyl groupsubstituted with unsubstituted C₁-C₆ alkyl and unsubstituted C₁-C₃alkoxy, a phenyl group substituted with unsubstituted C₁-C₃ alkoxy andhalogen, a phenyl group substituted with unsubstituted C₁-C₆ alkyl andunsubstituted di(C₁-C₃ alkyl)amino, or a phenyl group substituted withunsubstituted di(C₁-C₃ alkyl)amino and halogen.
 13. The method of claim7, wherein R₁ is L-Y and R₂ is H.
 14. The method of claim 13, wherein Lis


15. The method of claim 7, wherein one of R₁ and R₂ is hydrogen and theother of R₁ and R₂ is optionally substituted C₃-C₈ cycloalkyl.
 16. Themethod of claim 6, wherein the cancer is leukemia, lymphoma, multiplemyeloma, breast cancer, or lung cancer.
 17. A method of treating cancerassociated with a cytokine, aiolos, ikaros, helios, CK1a, or GSPT1,comprising administering a compound of Formula (IIc) or apharmaceutically acceptable salt thereof to a subject in need thereof,

wherein: one of R₁ and R₂ is H, deuterium, hydroxyl, halogen, cyano,nitro, optionally substituted amino, optionally substituted C₁-C₆alkoxy, optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted 3 to 10-membered

heterocyclyl, optionally substituted 5 to 10-membered heteroaryl, orL-Y; and the other of R₁ and R₂ is optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted 3to 10-membered heterocyclyl, optionally substituted 5 to 10-memberedheteroaryl, or L-Y;

provided that when one of R₁ and R₂ is then the other R₁ and R₂ is notL-Y; R₅ is H, deuterium, or optionally substituted C₁-C₆ alkyl; n is 2or 3; each of Qa and Qb is independently C═O, C=S, or CH₂; X is CH₂ orC(═O); X₁ is H, deuterium, halogen, or optionally substituted C₁-C₆alkyl; m is 1, 2, 3, 4, or 5; X₂ is (CH₂)_(a), C=0, NH, or N—(optionallysubstituted C₁-C₆ alkyl); X₃ is O, NH, or S; a is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; R₈ is optionally substituted C₃-C₁₀ cycloalkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to10-membered heteroaryl, optionally substituted 3 to 10-memberedheterocyclyl, optionally substituted C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl),optionally substituted C₆-C₁₀ aryl(C₁-C₆ alkyl), optionally substituted5 to 10 membered heteroaryl(C₁-C₆ alkyl), or optionally substituted 3 to10 membered heterocyclyl(C₁-C₆ alkyl);

each Z₁ and Z₂ is —CH₂—; each R₆ is independently absent or C₁-C₆ alkyl;and each Y is independently selected from a group consisting ofwherein * represents the point of attachment to the L group.


18. The method of claim 17, wherein n is 2; X¹ is H; R₅ is H; and Qa andQb are each C═O.
 19. The method of claim 18, wherein one of R₁ and R₂ is

hydrogen, and the other R₁ and R₂ is L-Y.
 20. The method of claim 18,wherein R₁ is H and R₂ is


21. The method of claim 20, wherein R₂ is

and X₂ is NH.
 22. The method of claim 21, wherein R₈ is a phenyl groupsubstituted with one or more substituents, each of which isindependently selected from the group consisting of halogen,unsubstituted C₁-C₆ alkyl, C₁-C₃ alkoxy, and unsubstituted di(C₁-C₃alkyl)amino; or a 5-6 membered heteroaryl group substituted with one ormore substituents each of which is independently selected from the groupconsisting of halogen, unsubstituted C₁-C₆ alkyl, C₁-C₃ alkoxy, andunsubstituted di(C₁-C₃ alkyl)amino.
 23. The method of claim 22, whereinR₈ is a phenyl group substituted with unsubstituted C₁-C₆ alkyl andhalogen, a phenyl group substituted with unsubstituted C₁-C₆ alkyl andunsubstituted C₁-C₃ alkoxy, a phenyl group substituted withunsubstituted C₁-C₃ alkoxy and halogen, a phenyl group substituted withunsubstituted C₁-C₆ alkyl and unsubstituted di(C₁-C₃ alkyl)amino, or aphenyl group substituted with unsubstituted di(C₁-C₃ alkyl)amino andhalogen.
 24. The method of claim 18, wherein R₁ is H and R₂ is L-Y. 25.The method of claim 24, wherein L is


26. The method of claim 18, wherein one of R₁ and R₂ is hydrogen and theother of R₁ and R₂ is optionally substituted C₃-C₈ cycloalkyl.
 27. Themethod of claim 17, wherein the cancer is leukemia, lymphoma, multiplemyeloma, breast cancer, or lung cancer.